Heteroaromatic quinoline compounds

ABSTRACT

The invention pertains to heteroaromatic compounds that serve as effective phosphodiesterase (PDE) inhibitors. In particular, the invention relates to said compounds which are selective inhibitors of PDE10. The invention also relates to intermediates for preparation of said compounds; pharmaceutical compositions comprising said compounds; and the use of said compounds in a method for treating certain central nervous system (CNS) or other disorders.

CROSS REFERENCE TO RELATED APPLICATION

The present application claims benefit of U.S. Ser. No. 60/642,058 filedon Jan. 7, 2005 which is incorporated by reference herein in itsentirety.

FIELD OF THE INVENTION

The invention pertains to heteroaromatic compounds that serve aseffective phosphodiesterase (PDE) inhibitors. The invention also relatesto compounds which are selective inhibitors of PDE10. The inventionfurther relates to intermediates for preparation of such compounds;pharmaceutical compositions comprising such compounds; and the use ofsuch compounds in methods for treating certain central nervous system(CNS) or other disorders. The invention relates also to methods fortreating neurodegenerative and psychiatric disorders, for examplepsychosis and disorders comprising deficient cognition as a symptom.

BACKGROUND OF INVENTION

Phosphodiesterases (PDEs) are a class of intracellular enzymes involvedin the hydrolysis of the nucleotides cyclic adenosine monophosphate(cAMP) and cyclic guanosine monophosphates (cGMP) into their respectivenucleotide monophosphates. The cyclic nucleotides cAMP and cGMP aresynthesized by adenylyl and guanylyl cyclases, respectively, and serveas secondary messengers in several cellular pathways.

The cAMP and cGMP function as intracellular second messengers regulatinga vast array of intracellular processes particularly in neurons of thecentral nervous system. In neurons, this includes the activation of cAMPand cGMP-dependent kinases and subsequent phosphorylation of proteinsinvolved in acute regulation of synaptic transmission as well as inneuronal differentiation and survival. The complexity of cyclicnucleotide signaling is indicated by the molecular diversity of theenzymes involved in the synthesis and degradation of cAMP and cGMP.There are at least ten families of adenylyl cyclases, two of guanylylcyclases, and eleven of phosphodiesterases. Furthermore, different typesof neurons are known to express multiple isozymes of each of theseclasses, and there is good evidence for compartmentalization andspecificity of function for different isozymes within a given neuron.

A principal mechanism for regulating cyclic nucleotide signaling is byphosphodiesterase-catalyzed cyclic nucleotide catabolism. There are 11known families of PDEs encoded by 21 different genes. Each genetypically yields multiple splice variants that further contribute to theisozyme diversity. The PDE families are distinguished functionally basedon cyclic nucleotide substrate specificity, mechanism(s) of regulation,and sensitivity to inhibitors. Furthermore, PDEs are differentiallyexpressed throughout the organism, including in the central nervoussystem. As a result of these distinct enzymatic activities andlocalization, different PDEs' isozymes can serve distinct physiologicalfunctions. Furthermore, compounds that can selectively inhibit distinctPDE families or isozymes may offer particular therapeutic effects, fewerside effects, or both.

PDE10 is identified as a unique family based on primary amino acidsequence and distinct enzymatic activity. Homology screening of ESTdatabases revealed mouse PDE10A as the first member of the PDE10 familyof PDEs (Fujishige et al., J. Biol. Chem. 274:18438-18445, 1999;Loughney, K. et al., Gene 234:109-117, 1999). The murine homologue hasalso been cloned (Soderling, S. et al., Proc. Natl. Acad. Sci. USA96:7071-7076, 1999)and N-terminal splice variants of both the rat andhuman genes have been identified (Kotera, J. et al., Biochem. Biophys.Res. Comm. 261:551-557, 1999; Fujishige, K. et al., Eur. J. Biochem.266:1118-1127, 1999). There is a high degree of homology across species.The mouse PDE10A1 is a 779 amino acid protein that hydrolyzes both cAMPand cGMP to AMP and GMP, respectively. The affinity of PDE10 for cAMP(Km=0.05 μM) is higher than for cGMP (Km=3 μM). However, theapproximately 5-fold greater Vmax for cGMP over cAMP has lead to thesuggestion that PDE10 is a unique cAMP-inhibited cGMPase (Fujishige etal., J. Biol. Chem. 274:18438-18445, 1999).

The PDE 10 family of polypeptides shows a lower degree of sequencehomology as compared to previously identified PDE families and has beenshown to be insensitive to certain inhibitors that are known to bespecific for other PDE families. U.S. Pat. No. 6,350,603, incorporatedherein by reference.

PDE10 also is uniquely localized in mammals relative to other PDEfamilies. mRNA for PDE10 is highly expressed only in testis and brain(Fujishige, K. et al., Eur J Biochem. 266:1118-1127, 1999; Soderling, S.et al., Proc. Natl. Acad. Sci. 96:7071-7076, 1999; Loughney, K. et al.,Gene 234:109-117, 1999). These initial studies indicated that within thebrain PDE10 expression is highest in the striatum (caudate and putamen),n. accumbens, and olfactory tubercle. More recently, a detailed analysishas been made of the expression pattern in rodent brain of PDE10 mRNA(Seeger, T. F. et al., Abst. Soc. Neurosci. 26:345.10, 2000) and PDE10protein (Menniti, F. S., Stick, C. A., Seeger, T. F., and Ryan, A. M.,Immunohistochemical localization of PDE10 in the rat brain. WilliamHarvey Research Conference ‘Phosphodiesterase in Health and Disease’,Porto, Portugal, Dec. 5-7, 2001).

A variety of therapeutic uses for PDE inhibitors has been reportedincluding obtrusive lung disease, allergies, hypertension, angina,congestive heart failure, depression and erectile dysfunction (WO01/41807 A2, incorporated herein by reference).

The use of selected benzimidazole and related heterocyclic compounds inthe treatment of ischemic heart conditions has been disclosed based uponinhibition of PDE associated cGMP activity. U.S. Pat. No. 5,693,652,incorporated herein by reference.

United States Patent Application Publication No. 2003/0032579 disclosesa method for treating certain neurologic and psychiatric disorders withthe selective PDE10 inhibitor papaverine. In particular, the methodrelates to psychotic disorders such as schizophrenia, delusionaldisorders and drug-induced psychosis; to anxiety disorders such as panicand obsessive-compulsive disorder; and to movement disorders includingParkinson's disease and Huntington's disease.

SUMMARY OF THE INVENTION

The present invention provides for compounds of formula I orpharmaceutical salts thereof,

wherein Z is

R₁ is each independently selected from a group consisting of hydrogen,halogen, hydroxyl, cyano, C₁ to C₈ alkyl, C₂ to C₈ alkenyl, C₂ to C₈alkynyl, C₁ to C₈ alkoxy, C₁ to C₈ haloalkyl, C₃ to C₈ cycloalkyl, C₃ toC₈ cycloalkyl-C₁ to C₈ alkyl, 4 to 7 membered heterocycloalkyl, C₁ to C₈alkylthio, —NR³R³, —O—CF₃, —S(O)_(n)—R³, C(O)—NR³R³, and C₁ to C₈ alkylsubstituted with a heteroatom wherein the heteroatom is selected from agroup consisting of nitrogen, oxygen and sulfur and wherein theheteroatom may be further substituted with a substituent selected from agroup consisting of hydrogen, C₁ to C₈ alkyl, C₃ to C₈ cycloalkyl, C₂ toC₈ alkenyl, C₂ to C₈ alkynyl, and C₁ to C₈ haloalkyl;

each R³ is independently selected from a group consisting of hydrogen,C₁ to C₈ alkyl, C₂ to C₈ alkenyl, C₂ to C₈ alkynyl, C₁ to C₈ haloalkyl,C₃ to C₈ cycloalkyl;

R² is selected from the group consisting of hydrogen, C₁ to C₈ alkyl, C₃to C₈ cycloalkyl-C₁ to C₈ alkyl, C₂ to C₈ alkenyl, C₂ to C₈ alkynyl, C₁to C₈ haloalkyl and C₃ to C₈ cycloalkyl;

HET¹ is selected from a group consisting of a monocyclic heteroaryl anda bicyclic heteroaryl, wherein the monocyclic and bicyclic heteroarylmay be optionally substituted with at least one R⁴ and;

R⁴ is selected from a group consisting of halogen, hydroxyl, cyano, C₁to C₈ alkyl, C₂ to C₈ alkenyl, C₂ to C₈ alkynyl, C₁ to C₈ alkoxy, C₃ toC₈ cycloalkyl, C₃ to C₈ cycloalkyl-C₁ to C₈ alkyl, C₁ to C₈ alkylthio,and C₁ to C₈ alkyl substituted with a substituent is selected from thegroup consisting of —OR⁸, —NR⁸R⁸, and —SR⁸, wherein R⁸ is independentlyselected from the group consisting of hydrogen and C₁ to C₈ alkyl

HET² is a monocyclic or bicyclic heteroaryl, wherein the monocyclic andbicyclic heteroaryl optionally substituted with at least one R⁵, withthe proviso that HET² is not tetrazole;

R⁵ is independently selected from a group consisting of halogen,hydroxyl, cyano, C¹ to C₈ alkyl, C₂ to C₈ alkenyl, C₂ to C₈ alkynyl, C₁to C₈ alkoxy, C₃ to C₈ cycloalkyl, C₃ to C₈ cycloalkyl-C₁ to C₈ alkyl,C₁ to C₈ alkylthio, —NR⁷R⁷ and C₁ to C₈ haloalkyl;

B¹ and B² are adjacent atoms in Het¹ which are independently selectedfrom a group consisting of carbon and nitrogen;

bond j is a covalent bond between Z and B²;

bond k is a covalent bond in Het¹ between B¹ and B²;

X and X¹ are each independently selected from the group consisting ofoxygen, sulfur, C(R₂)₂ and NR₂; provided that at least one of X or X¹ iscarbon;

Y is selected from a group consisting of carbon and nitrogen, providedthat when Y is carbon it is substituted with R⁶;

wherein each R⁶ is independently selected from a group consisting ofhydrogen, halogen, hydroxyl, cyano, C₁ to C₈ alkyl, C₂ to C₈ alkenyl, C₂to C₈ alkynyl, C₁ to C₈ alkoxy, C₁ to C₈ cycloalkyl, C₃ to C₈cycloalkyl-C₁ to C₈ alkyl, C₁ to C₈ alkylthio, C₁ to C₈ haloalkyl,—NR⁷R⁷, —O—CF₃, —S(O)m-R⁷, and C(O)—NR⁷R⁷, C₁ to C₈ alkyl substitutedwith a heteroatom wherein the heteroatom is selected from a groupconsisting of nitrogen, oxygen and sulfur and wherein the heteroatom maybe further substituted with a substituent selected from the groupconsisting of hydrogen, C₁ to C₈ alkyl, C₃ to C₈ cycloalkyl, C₂ to C₈alkenyl, C₂ to C₈ alkynyl and C₁ to C₈ haloalkyl;

wherein each R⁷ is independently selected from the group consisting ofhydrogen and C₁-C₈ alkyl; p is 1, 2 or 3; n is 0, 1 or 2; and m is 0, 1or 2.

In another embodiment, the present invention provides for compounds offormula I or pharmaceutical salts thereof;

wherein Z is

R¹ is each independently selected from a group consisting of hydrogen,halogen, hydroxyl, cyano, C₁ to C₈ alkyl, C₂ to C₈ alkenyl, C₂ to C₈alkynyl, C₁ to C₈ alkoxy, C₁ to C₈ haloalkyl, C₃ to C₈ cycloalkyl, C₃ toC₈ cycloalkyl-C₁ to C₈ alkyl, 4 to 7 membered heterocycloalkyl, C₁ to C₈alkylthio, —NR³R³, —O—CF₃, —S(O)_(n)—R³, C(O)—NR³R³, and C₁ to C₈ alkylsubstituted with a heteroatom wherein the heteroatom is selected from agroup consisting of nitrogen, oxygen and sulfur and wherein theheteroatom may be further substituted with a substituent selected from agroup consisting of hydrogen, C₁ to C₈ alkyl, C₃ to C₈ cycloalkyl, C₂ toC₈ alkenyl, C₂ to C₈ alkynyl, and C₁ to C₈ haloalkyl;

each R³ is independently selected from a group consisting of hydrogen,C₁ to C₈ alkyl, C₂ to C₈ alkenyl, C₂ to C₈ alkynyl, C₁ to C₈ haloalkyl,C₃ to C₈ cycloalkyl;

R² is selected from the group consisting of hydrogen, C₁ to C₈ alkyl, C₃to C₈ cycloalkyl-C₁ to C₈ alkyl, C₂ to C₈ alkenyl, C₂ to C₈ alkynyl C₂to C₈ alkenyl, C₁ to C₈ haloalkyl and C₃ to C₈ cycloalkyl;

HET¹ is selected from a group consisting of a monocyclic heteroaryl anda bicyclic heteroaryl, wherein the monocyclic and bicyclic heteroarylmay be optionally substituted with at least one R⁴;

R⁴ is selected from a group consisting of C₁ to C₈ haloalkyl;

HET² is a monocyclic or bicyclic heteroaryl, wherein the monocyclic andbicyclic heteroaryl and may be substituted with at least one R⁵;

R⁵ is independently selected from a group consisting of halogen,hydroxyl, cyano, C₁ to C₈ alkyl, C₂ to C₈ alkenyl, C₂ to C₈ alkynyl, C₁to C₈ alkoxy, C₃ to C₈ cycloalkyl, C₃ to C₈ cycloalkyl-C₁ to C₈ alkyl,C₁ to C₈ alkylthio, —NR⁷R⁷, and C₁ to C₈ haloalkyl;

B¹ and B² are adjacent atoms in Het¹ which are independently selectedfrom a group consisting of carbon and nitrogen;

bond j is a covalent bond between Z and B²;

bond k is a bond in Het¹ between B¹ and B²;

X and X¹ are each independently selected from the group consisting ofoxygen, sulfur, C(R₂)₂ and NR₂, provided that at least one of X or X¹ iscarbon;

Y is selected from a group consisting of carbon and nitrogen, providedthat when Y is carbon it is substituted with R⁶;

wherein each R₆ is independently selected from a group consisting ofhydrogen, halogen, hydroxyl, cyano, C₁ to C₈ alkyl, C₂ to C₈ alkenyl, C₂to C₈ alkynyl, C₁ to C₈ alkoxy, C₁ to C₈ cycloalkyl, C₃ to C₈cycloalkyl-C₁ to C₈ alkyl, C₁ to C₈ alkylthio, C₁ to C₈ haloalkyl,NR⁷R⁷—O—CF₃, —S(O)m-R⁷, and C(O)—NR⁷R⁷. C₁ to C₈ alkyl substituted witha heteroatom wherein the heteroatom is selected from a group consistingof nitrogen, oxygen and sulfur and wherein the heteroatom may be furthersubstituted with a substituent selected from the group consisting ofhydrogen, C₁ to C₈ alkyl, C₃ to C₈ cycloalkyl, C₂ to C₈ alkenyl, C₂ toC₈ alkynyl, and C₁ to C₈ haloalkyl;

wherein each R⁷ is independently selected from the group consisting ofhydrogen and C₁-C₈alkyl; p is 1, 2 or 3; n is 0, 1 or 2 and m is 0, 1 or2.

In one aspect of the present invention, Y is selected from a groupconsisting of carbon and nitrogen, provided that not more than one Y isnitrogen.

In another aspect of the present invention, X¹ is carbon and X isoxygen.

In another aspect of the present invention all Y's are carbon (i.e., theheteroaryl is quinoline).

The present invention also provides compounds of formula I orpharmaceutical salts thereof, wherein HET¹ is a 5 membered heteroarylgroup. Preferably, HET¹ is selected from a group consisting of pyrazole,isoxazole, triazole, oxazole, thiazole and imidazole.

The present invention also provides subgenera providing for number ofring members for HET² of formula I wherein HET² is selected from a groupconsisting of 4-pyridyl, 4-pyridazine and isoxazole. More preferably,HET² is 4-pyridyl.

In a preferred embodiment, the invention is directed to a compound offormula I(a)-I(k):

wherein j, k, Z HET²and R⁴ are as defined above. More preferably, thecompounds of formula I have the following general structure:

Most preferably, the compounds of formula I have the following generalstructure:

In another aspect, for the above compounds of Formula I, HET¹ is nottetrazole.

Compounds of the Formula I may have optical centers and therefore mayoccur in different enantiomeric and diastereomeric configurations. Thepresent invention includes all enantiomers, diastereomers, and otherstereoisomers of such compounds of the Formula I, as well as racemiccompounds and racemic mixtures and other mixtures of stereoisomersthereof.

Pharmaceutically acceptable salts of the compounds of Formula I includethe acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include, but are not limited to, the acetate, adipate,aspartate, benzoate, besylate, bicarbonate/carbonate,bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate,esylate, formate, fumarate, gluceptate, gluconate, glucuronate,hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mandelates mesylate, methylsulphate, naphthylate,2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate,salicylate, saccharate, stearate, succinate, sulfonate, stannate,tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include, but are not limited to, the aluminium, arginine,benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine,magnesium, meglumine, olamine, potassium, sodium, tromethamine and zincsalts.

Hemisalts of acids and bases may also be formed, for example,hemisulphate and hemicalcium salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts:Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of compounds of Formula I may beprepared by one or more of three methods:

(i) by reacting the compound of Formula I with the desired acid or base;

(ii) by removing an acid- or base-labile protecting group from asuitable precursor of the compound of Formula I or by ring-opening asuitable cyclic precursor, for example, a lactone or lactam, using thedesired acid or base; or

(iii) by converting one salt of the compound of Formula I to another byreaction with an appropriate acid or base or by means of a suitable ionexchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionization in theresulting salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in a continuum of solid statesranging from fully amorphous to fully crystalline. The term ‘amorphous’refers to a state in which the material lacks long range order at themolecular level and, depending upon temperature, may exhibit thephysical properties of a solid or a liquid. Typically such materials donot give distinctive X-ray diffraction patterns and, while exhibitingthe properties of a solid, are more formally described as a liquid. Uponheating, a change from solid to liquid properties occurs which ischaracterised by a change of state, typically second order (‘glasstransition’). The term ‘crystalline’ refers to a solid phase in whichthe material has a regular ordered internal structure at the molecularlevel and gives a distinctive X-ray diffraction pattern with definedpeaks. Such materials when heated sufficiently will also exhibit theproperties of a liquid, but the change from solid to liquid ischaracterised by a phase change, typically first order (‘meltingpoint’).

The compounds of the invention may also exist in unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol. Theterm ‘hydrate’ is employed when said solvent is water.

A currently accepted classification system for organic hydrates is onethat defines isolated site, channel, or metal-ion coordinatedhydrates—see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed.H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones inwhich the water molecules are isolated from direct contact with eachother by intervening organic molecules. In channel hydrates, the watermolecules lie in lattice channels where they are next to other watermolecules. In metal-ion coordinated hydrates, the water molecules arebonded to the metal iron.

When the solvent or water is tightly bound, the complex will have awell-defined stoichiometry independent of humidity. When, however, thesolvent or water is weakly bound, as in channel solvates and hygroscopiccompounds, the water/solvent content will be dependent on humidity anddrying conditions. In such cases, non-stoichiometry will be the norm.

The compounds of the invention may also exist in a mesomorphic state(mesophase or liquid crystal) when subjected to suitable conditions. Themesomorphic state is intermediate between the true crystalline state andthe true liquid state (either melt or solution). Mesomorphism arising asthe result of a change in temperature is described as ‘thermotropic’ andthat resulting from the addition of a second component, such as water oranother solvent, is described as ‘lyotropic’. Compounds that have thepotential to form lyotropic mesophases are described as ‘amphiphilic’and consist of molecules which possess an ionic (such as —COO⁻Na⁺,—COO⁻K⁺, or —SO₃ ⁻Na⁺) or non-ionic (such as —N⁻N⁺(CH₃)₃) polar headgroup. For more information, see Crystals and the Polarizing Microscopeby N. H. Hartshorne and A. Stuart, 4^(th) Edition (Edward Arnold, 1970).

Hereinafter all references to compounds of Formula I include referencesto salts, solvates, multi-component complexes and liquid crystalsthereof and to solvates, multi-component complexes and liquid crystalsof salts thereof.

The compounds of the invention include compounds of Formula I ashereinbefore defined, including all polymorphs and crystal habitsthereof, prodrugs and isomers thereof (including optical, geometric andtautomeric isomers) as hereinafter defined and isotopically-labeledcompounds of Formula I.

As indicated, so-called ‘prodrugs’ of the compounds of Formula I arealso within the scope of the invention. Thus certain derivatives ofcompounds of Formula I which may have little or no pharmacologicalactivity themselves can, when administered into or onto the body, beconverted into compounds of Formula I having the desired activity, forexample, by hydrolytic cleavage. Such derivatives are referred to as‘prodrugs’. Further information on the use of prodrugs may be found inPro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T.Higuchi and W. Stella) and Bioreversible Carriers in Drug Design,Pergamon Press, 1987 (Ed. E. B. Roche, American PharmaceuticalAssociation).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds ofFormula I with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in Design of Prodrugs by H.Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include, butare not limited to,

(i) where the compound of Formula I contains a carboxylic acidfunctionality (—COOH), an ester thereof, for example, a compound whereinthe hydrogen of the carboxylic acid functionality of the compound ofFormula (I) is replaced by (C₁-C₈)alkyl;

(ii) where the compound of Formula I contains an alcohol functionality(—OH), an ether thereof, for example, a compound wherein the hydrogen ofthe alcohol functionality of the compound of Formula I is replaced by(C₁-C₆)alkanoyloxymethyl; and

(iii) where the compound of Formula I contains a primary or secondaryamino functionality (—NH₂ or —NHR where R≠H), an amide thereof, forexample, a compound wherein, as the case may be, one or both hydrogensof the amino functionality of the compound of Formula I is/are replacedby (C₁-C₁₀)alkanoyl.

Further examples of replacement groups in accordance with the foregoingexamples and examples of other prodrug types may be found in theaforementioned references.

Moreover, certain compounds of Formula I may themselves act as prodrugsof other compounds of Formula I.

Also included within the scope of the invention are metabolites ofcompounds of Formula I, that is, compounds formed in vivo uponadministration of the drug. Some examples of metabolites in accordancewith the invention include, but are not limited to,

(i) where the compound of Formula I contains a methyl group, anhydroxymethyl derivative thereof (—CH₃->—CH₂OH):

(ii) where the compound of Formula I contains an alkoxy group, anhydroxy derivative thereof (—OR->—OH);

(iii) where the compound of Formula I contains a tertiary amino group, asecondary amino derivative thereof (—NR¹R²->—NHR¹ or —NHR²);

(iv) where the compound of Formula I contains a secondary amino group, aprimary derivative thereof (—NHR¹->—NH₂);

(v) where the compound of Formula I contains a phenyl moiety, a phenolderivative thereof (-Ph->-PhOH); and

(vi) where the compound of Formula I contains an amide group, acarboxylic acid derivative thereof (—CONH₂->COOH);

(vii) where the compound contains an aromatic nitrogen atom or antetrtiary aliphatic amine function, an N-oxide derivative thereof.

Compounds of Formual I having a nitrogen atom in a tertiary aminefunctional group may be further substituted with oxygen (i.e., anN-oxide);

Compounds of Formula I containing one or more asymmetric carbon atomscan exist as two or more stereoisomers. Where a compound of Formula Icontains an alkenyl or alkenylene group, geometric cis/trans (or Z/E)isomers are possible. Where structural isomers are interconvertible viaa low energy barrier, tautomeric isomerism (‘tautomerism’) can occur.This can take the form of proton tautomerism in compounds of Formula Icontaining, for example, an imino, keto, or oxime group, or so-calledvalence tautomerism in compounds that contain an aromatic moiety. Itfollows that a single compound may exhibit more than one type ofisomerism.

Included within the scope of the present invention are allstereoisomers, geometric isomers and tautomeric forms of the compoundsof Formula I, including compounds exhibiting more than one type ofisomerism, and mixtures of one or more thereof. Also included are acidaddition or base salts wherein the counterion is optically active, forexample, d-lactate or l-lysine, or racemic, for example, dl-tartrate ordl-arginine.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallisation.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of Formula I contains an acidic or basicmoiety, a base or acid such as 1-phenylethylamine or tartaric acid. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50% byvolume of isopropanol, typically from 2% to 20%, and from 0 to 5% byvolume of an alkylamine, typically 0.1% diethylamine. Concentration ofthe eluate affords the enriched mixture.

When any racemate crystallises, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

While both of the crystal forms present in a racemic mixture haveidentical physical properties, they may have different physicalproperties compared to the true racemate. Racemic mixtures may beseparated by conventional techniques known to those skilled in theart—see, for example, Stereochemistry of Organic Compounds by E. L.Eliel and S. H. Wilen (Wiley, 1994).

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of Formula I wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number whichpredominates in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include, but are not limited to, isotopes of hydrogen, such as²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl,fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P,and sulphur, such as ³⁵S.

Certain isotopically-labelled compounds of Formula I, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of Formula I can generally be prepared byconventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagent in placeof the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Specific embodiments of the present invention include the compoundsexemplified in the Examples below and their pharmaceutically acceptablesalts, complexes, solvates, polymorphs, steroisomers, metabolites,prodrugs, and other derivatives thereof;

This invention also pertains to a pharmaceutical composition fortreatment of certain psychotic disorders and conditions such asschizophrenia, delusional disorders and drug induced psychosis; toanxiety disorders such as panic and obsessive-compulsive disorder; andto movement disorders including Parkinson's disease and Huntington'sdisease, comprising an amount of a compound of formula I effective ininhibiting PDE 10.

In another embodiment, this invention relates to a pharmaceuticalcomposition for treating psychotic disorders and condition such asschizophrenia, delusional disorders and drug induced psychosis; anxietydisorders such as panic and obsessive-compulsive disorder; and movementdisorders including Parkinson's disease and Huntington's disease,comprising an amount of a compound of formula I effective in treatingsaid disorder or condition.

Examples of psychotic disorders that can be treated according to thepresent invention include, but are not limited to, schizophrenia, forexample of the paranoid, disorganized, catatonic, undifferentiated, orresidual type; schizophreniform disorder; schizoaffective disorder, forexample of the delusional type or the depressive type; delusionaldisorder; substance-induced psychotic disorder, for example psychosisinduced by alcohol, amphetamine, cannabis, cocaine, hallucinogens,inhalants, opioids, or phencyclidine; personality disorder of theparanoid type; and personality disorder of the schizoid type.

Examples of movement disorders that can be treated according to thepresent invention include but are not limited to selected fromHuntington's disease and dyskinesia associated with dopamine agonisttherapy, Parkinson's disease, restless leg syndrome, and essentialtremor.

Other disorders that can be treated according to the present inventionare obsessive/compulsive disorders, Tourette's syndrome and other ticdisorders.

In another embodiment, this invention relates to a method for treatingan anxiety disorder or condition in a mammal which method comprisesadministering to said mammal an amount of a compound of formula Ieffective in inhibiting PDE 10.

This invention also provides a method for treating an anxiety disorderor condition in a mammal which method comprises administering to saidmammal an amount of a compound of formula I effective in treating saiddisorder or condition.

Examples of anxiety disorders that can be treated according to thepresent invention include, but are not limited to, panic disorder;agoraphobia; a specific phobia; social phobia; obsessive-compulsivedisorder; post-traumatic stress disorder; acute stress disorder; andgeneralized anxiety disorder.

This invention further provides a method of treating a drug addiction,for example an alcohol, amphetamine, cocaine, or opiate addiction, in amammal, including a human, which method comprises administering to saidmammal an amount of a compound of formula I effective in treating drugaddiction.

This invention also provides a method of treating a drug addiction, forexample an alcohol, amphetamine, cocaine, or opiate addiction, in amammal, including a human, which method comprises administering to saidmammal an amount of a compound of formula I effective in inhibitingPDE10.

A “drug addiction”, as used herein, means an abnormal desire for a drugand is generally characterized by motivational disturbances such acompulsion to take the desired drug and episodes of intense drugcraving.

This invention further provides a method of treating a disordercomprising as a symptom a deficiency in attention and/or cognition in amammal, including a human, which method comprises administering to saidmammal an amount of a compound of formula I effective in treating saiddisorder.

This invention also provides a method of treating a disorder orcondition comprising as a symptom a deficiency in attention and/orcognition in a mammal, including a human, which method comprisesadministering to said mammal an amount of a compound of formula Ieffective in inhibiting PDE10.

This invention also provides a method of treating a disorder orcondition comprising as a symptom a deficiency in attention and/orcognition in a mammal, including a human, which method comprisesadministering to said mammal an amount of a compound of formula Ieffective in treating said disorder or condition.

The phrase “deficiency in attention and/or cognition” as used herein in“disorder comprising as a symptom a deficiency in attention and/orcognition” refers to a subnormal functioning in one or more cognitiveaspects such as memory, intellect, or learning and logic ability, in aparticular individual relative to other individuals within the samegeneral age population. “Deficiency in attention and/or cognition” alsorefers to a reduction in any particular individual's functioning in oneor more cognitive aspects, for example as occurs in age-relatedcognitive decline.

Examples of disorders that comprise as a symptom a deficiency inattention and/or cognition that can be treated according to the presentinvention are dementia, for example Alzheimer's disease, multi-infarctdementia, alcoholic dementia or other drug-related dementia, dementiaassociated with intracranial tumors or cerebral trauma, dementiaassociated with Huntington's disease or Parkinson's disease, orAIDS-related dementia; delirium; amnestic disorder; post-traumaticstress disorder; mental retardation; a learning disorder, for examplereading disorder, mathematics disorder, or a disorder of writtenexpression; attention-deficit/hyperactivity disorder; and age-relatedcognitive decline.

This invention also provides a method of treating a mood disorder ormood episode in a mammal, including a human, comprising administering tosaid mammal an amount of a compound of formula I effective in treatingsaid disorder or episode.

This invention also provides a method of treating a mood disorder ormood episode in a mammal, including a human, comprising administering tosaid mammal an amount of a compound of formula I effective in inhibitingPDE10.

Examples of mood disorders and mood episodes that can be treatedaccording to the present invention include, but are not limited to,major depressive episode of the mild, moderate or severe type, a manicor mixed mood episode, a hypomanic mood episode; a depressive episodewith atypical features; a depressive episode with melancholic features;a depressive episode with catatonic features; a mood episode withpostpartum onset; post-stroke depression; major depressive disorder;dysthymic disorder; minor depressive disorder; premenstrual dysphoricdisorder; post-psychotic depressive disorder of schizophrenia; a majordepressive disorder superimposed on a psychotic disorder such asdelusional disorder or schizophrenia; a bipolar disorder, for examplebipolar I disorder, bipolar II disorder, and cyclothymic disorder.

This invention further provides a method of treating a neurodegenerativedisorder or condition in a mammal, including a human, which methodcomprises administering to said mammal an amount of a compound offormula I effective in treating said disorder or condition.

This invention further provides a method of treating a neurodegenerativedisorder or condition in a mammal, including a human, which methodcomprises administering to said mammal an amount of a compound offormula I effective in inhibiting PDE10.

As used herein, and unless otherwise indicated, a “neurodegenerativedisorder or condition” refers to a disorder or condition that is causedby the dysfunction and/or death of neurons in the central nervoussystem. The treatment of these disorders and conditions can befacilitated by administration of an agent which prevents the dysfunctionor death of neurons at risk in these disorders or conditions and/orenhances the function of damaged or healthy neurons in such a way as tocompensate for the loss of function caused by the dysfunction or deathof at-risk neurons. The term “neurotrophic agent” as used herein refersto a substance or agent that has some or all of these properties.

Examples of neurodegenerative disorders and conditions that can betreated according to the present invention include, but are not limitedto, Parkinson's disease; Huntington's disease; dementia, for exampleAlzheimer's disease, multi-infarct dementia, AIDS-related dementia, andFronto temperal Dementia; neurodegeneration associated with cerebraltrauma; neurodegeneration associated with stroke, neurodegenerationassociated with cerebral infarct; hypoglycemia-inducedneurodegeneration; neurodegeneration associated with epileptic seizure;neurodegeneration associated with neurotoxin poisoning; and multi-systematrophy.

In one embodiment of the present invention, the neurodegenerativedisorder or condition comprises neurodegeneration of striatal mediumspiny neurons in a mammal, including a human.

In a further embodiment of the present invention, the neurodegenerativedisorder or condition is Huntington's disease.

This invention also provides a pharmaceutical composition for treatingpsychotic disorders, delusional disorders and drug induced psychosis;anxiety disorders, movement disorders, mood disorders, neurodegenerativedisorders, obesity, and drug addiction, comprising an amount of acompound of formula I effective in treating said disorder or condition.

This invention also provides a method of treating a disorder selectedfrom psychotic disorders, delusional disorders and drug inducedpsychosis; anxiety disorders, movement disorders, obesity, mooddisorders, and neurodegenerative disorders, which method comprisesadministering an amount of a compound of formula I effective in treatingsaid disorder.

This invention also provides a method of treating disorders selectedfrom the group consisting of: dementia, Alzheimer's disease,multi-infarct dementia, alcoholic dementia or other drug-relateddementia, dementia associated with intracranial tumors or cerebraltrauma, dementia associated with Huntington's disease or Parkinson'sdisease, or AIDS-related dementia; delirium; amnestic disorder;post-traumatic stress disorder; mental retardation; a learning disorder,for example reading disorder, mathematics disorder, or a disorder ofwritten expression; attention-deficit/hyperactivity disorder;age-related cognitive decline, major depressive episode of the mild,moderate or severe type; a manic or mixed mood episode; a hypomanic moodepisode; a depressive episode with atypical features; a depressiveepisode with melancholic features; a depressive episode with catatonicfeatures; a mood episode with postpartum onset; post-stroke depression;major depressive disorder; dysthymic disorder; minor depressivedisorder; premenstrual dysphoric disorder; post-psychotic depressivedisorder of schizophrenia; a major depressive disorder superimposed on apsychotic disorder comprising a delusional disorder or schizophrenia; abipolar disorder comprising bipolar I disorder, bipolar II disorder,cyclothymic disorder, Parkinson's disease; Huntington's disease;dementia, Alzheimer's disease, multi-infarct dementia, AIDS-relateddementia, Fronto temperal Dementia; neurodegeneration associated withcerebral trauma; neurodegeneration associated with stroke;neurodegeneration associated with cerebral infarct; hypoglycemia-inducedneurodegeneration; neurodegeneration associated with epileptic seizure;neurodegeneration associated with neurotoxin poisoning; multi-systematrophy, paranoid, disorganized, catatonic, undifferentiated or residualtype; schizophreniform disorder; schizoaffective disorder of thedelusional type or the depressive type; delusional disorder;substance-induced psychotic disorder, psychosis induced by alcohol,amphetamine, cannabis, cocaine, hallucinogens, obesity, inhalants,opioids, or phencyclidine; personality disorder of the paranoid type;and personality disorder of the schizoid type, which method comprisesadministering an amounot of a compound of Formula I effecting in saiddisorders.

This invention also provides a method of treating psychotic disorders,delusional disorders and drug induced psychosis; anxiety disorders,movement disorders, mood disorders, neurodegenerative disorders,obesity, and drug addiction which method comprises administering anamount of a compound of formula I effective in inhibiting PDE10.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight or branchedmoieties. Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl, isopropyl, and t-butyl.

The term “alkenyl”, as used herein, unless otherwise indicated, includesalkyl moieties having at least one carbon-carbon double bond whereinalkyl is as defined above. Examples of alkenyl include, but are notlimited to, ethenyl and propenyl.

The term “alkynyl”, as used herein, unless otherwise indicated, includesalkyl moieties having at least one carbon-carbon triple bond whereinalkyl is as defined above. Examples of alkynyl groups include, but arenot limited to, ethynyl and 2-propynyl.

The term “alkoxy”, as used herein, unless otherwise indicated, asemployed herein alone or as part of another group refers to an alkyl,groups linked to an oxygen atom.

The term “alkylthio” as used herein, unless otherwise indicated,employed herein alone or as part of another group includes any of theabove alkyl groups linked through a sulfur atom.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine.

The term “haloalkyl” as used herein, unless otherwise indicated, refersto at least one halo group, linked to an alkyl group. Examples, ofhaloalkyl groups include, but are not limited, to trifluoromethyl,trifluoroethyl, difluoromethyl and fluoromethyl groups.

The term “cycloalkyl”, as used herein, unless otherwise indicated,includes non-aromatic saturated cyclic alkyl moieties wherein alkyl isas defined above. Examples of cycloalkyl include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The term “aryl”, as used herein, unless otherwise indicated, includes anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl, naphthyl, indenyl, and fluorenyl. “Aryl”encompasses fused ring groups wherein at least one ring is aromatic.

The terms “heterocyclic”, “heterocycloalkyl”, and like terms, as usedherein, refer to non-aromatic cyclic groups containing one or moreheteroatoms, prefereably from one to four heteroatoms, each preferablyselected from oxygen, sulfur and nitrogen. The heterocyclic groups ofthis invention can also include ring systems substituted with one ormore oxo moieties. Examples of non-aromatic heterocyclic groups areaziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl,piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl,pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, quinolizinyl, quinuclidinyl,1,4-dioxaspiro[4.5]decyl, 1,4-dioxaspiro[4.4]nonyl,1,4-dioxaspiro[4.3]octyl, and 1,4-dioxaspiro[4.2]heptyl.

The term “heteroaryl”, as used herein, refers to aromatic groupscontaining one or more heteroatoms (preferably oxygen, sulfur andnitrogen), preferably from one to four heteroatoms. A multicyclic groupcontaining one or more heteroatoms wherein at least one ring of thegroup is aromatic is a “heteroaryl” group. The heteroaryl groups of thisinvention can also include ring systems substituted with one or more oxomoieties. Heteroaryl groups containing a tertiary nitrogen may also befurther substituted with oxygen (i.e., an N-oxide). Examples ofheteroaryl groups are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl,pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl,thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl,dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl,pyrolopyrimidinyl, and azaindolyl. For clarity, the term heteroarylincludes the heteroaryl structure in substituent Z in Formula I (i.e.,the heteroaryl structure containing Y).

Unless otherwise indicated, the term “one or more” substituents, or “atleast one” substituent as used herein, refers to from one to the maximumnumber of substituents possible based on the number of available bondingsites.

Unless otherwise indicated, all the foregoing groups derived fromhydrocarbons may have up to about 1 to about 20 carbon atoms (e.g.C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₃-C₂₀ cycloalkyl, 3-20 memberedheterocycloalkyl; C₆-C₂₀ aryl, 5-20 membered heteroaryl, etc.) or 1 toabout 15 carbon atoms (e.g., C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl, C₃-C₁₅cycloalkyl, 3-15 membered heterocycloalkyl, C₆-C₁₅ aryl, 5-15 memberedheteroaryl, etc.) , or 1 to about 12 carbon atoms, or 1 to about 8carbon atoms, or 1 to about 6 carbon atoms.

“Neurotoxin poisoning” refers to poisoning caused by a neurotoxin. Aneurotoxin is any chemical or substance that can cause neural death andthus neurological damage. An example of a neurotoxin is alcohol, which,when abused by a pregnant female, can result in alcohol poisoning andneurological damage known as Fetal Alcohol Syndrome in a newborn. Otherexamples of neurotoxins include, but are not limited to, kainic acid,domoic acid, and acromelic acid; certain pesticides, such as DDT;certain insecticides, such as organophosphates; volatile organicsolvents such as hexacarbons (e.g. toluene); heavy metals (e.g. lead,mercury, arsenic, and phosphorous); aluminum; certain chemicals used asweapons, such as Agent Orange and Nerve Gas; and neurotoxicantineoplastic agents.

As used herein, the term “selective PDE10 inhibitor” refers to asubstance, for example an organic molecule, that effectively inhibits anenzyme from the PDE10 family to a greater extent than enzymes from thePDE 1-9 families or PDE11 family. In one embodiment, a selective PDE10inhibitor is a substance, for example an organic molecule, having aK_(i) for inhibition of PDE10 that is less than or about one-tenth theK_(i) that the substance has for inhibition of any other PDE enzyme. Inother words, the substance inhibits PDE10 activity to the same degree ata concentration of about one-tenth or less than the concentrationrequired for any other PDE enzyme.

In general, a substance is considered to effectively inhibit PDE10activity if it has a K_(i) of less than or about 10 μM, preferably lessthan or about 0.1 μM.

A “selective PDE10 inhibitor” can be identified, for example, bycomparing the ability of a substance to inhibit PDE10 activity to itsability to inhibit PDE enzymes from the other PDE families. For example,a substance may be assayed for its ability to inhibit PDE10 activity, aswell as PDE1A, PDE1B, PDE1C, PDE2, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C,PDE4D, PDE5, PDE6, PDE7, PDE8, PDE9, and PDE11.

The term “treating”, as in “a method of treating a disorder”, refers toreversing, alleviating, or inhibiting the progress of the disorder towhich such term applies, or one or more symptoms of the disorder. Asused herein, the term also encompasses, depending on the condition ofthe patient, preventing the disorder, including preventing onset of thedisorder or of any symptoms associated therewith, as well as reducingthe severity of the disorder or any of its symptoms prior to onset.“Treating” as used herein refers also to preventing a recurrence of adisorder.

For example, “treating schizophrenia, or schizophreniform orschizoaffective disorder” as used herein also encompasses treating oneor more symptoms (positive, negative, and other associated features) ofsaid disorders, for example treating, delusions and/or hallucinationassociated therewith. Other examples of symptoms of schizophrenia andschizophreniform and schizoaffecctive disorders include disorganizedspeech, affective flattening, alogia, anhedonia, inappropriate affect,dysphoric mood (in the form of, for example, depression, anxiety oranger), and some indications of cognitive dysfunction.

The term “mammal”, as used herein, refers to any member of the class“Mammalia”, including, but not limited to, humans, dogs, and cats.

The compound of the invention may be administered either alone or incombination with pharmaceutically acceptable carriers, in either singleor multiple doses. Suitable pharmaceutical carriers include inert soliddiluents or fillers, sterile aqueous solutions and various organicsolvents. The pharmaceutical compositions formed thereby can then bereadily administered in a variety of dosage forms such as tablets,powders, lozenges, liquid preparations, syrups, injectable solutions andthe like. These pharmaceutical compositions can optionally containadditional ingredients such as flavorings, binders, excipients and thelike. Thus, the compound of the invention may be formulated for oral,buccal, intranasal, parenteral (e.g. intravenous, intramuscular orsubcutaneous), transdermal (e.g. patch) or rectal administration, or ina form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium phosphate); lubricants (e.g. magnesium stearate, talc orsilica); disintegrants (e.g. potato starch or sodium starch glycolate);or wetting agents (e.g. sodium lauryl sulphate). The tablets may becoated by methods well known in the art. Liquid preparations for oraladministration may take the form of, for example, solutions, syrups orsuspensions, or they may be presented as a dry product for constitutionwith water or other suitable vehicle before use. Such liquidpreparations may be prepared by conventional means with pharmaceuticallyacceptable additives such as suspending agents (e.g. sorbitol syrup,methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g.lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily estersor ethyl alcohol); and preservatives (e.g. methyl or propylp-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g. in ampules or in multi-dosecontainers, with an added preservative. They may take such forms assuspensions, solutions or emulsions in oily or aqueous vehicles, and maycontain formulating agents such as suspending, stabilizing and/ordispersing agents. Alternatively, the active ingredient may be in powderform for reconstitution with a suitable vehicle, e.g. sterilepyrogen-free water, before use.

When a product solution is required, it can be made by dissolving theisolated inclusion complex in water (or other aqueous medium) in anamount sufficient to generate a solution of the required strength fororal or parenteral administration to patients. The compounds may beformulated for fast dispersing dosage forms (fddf), which are designedto release the active ingredient in the oral cavity. These have oftenbeen formulated using rapidly soluble gelatin-based matrices. Thesedosage forms are well known and can be used to deliver a wide range ofdrugs. Most fast dispersing dosage forms utilize gelatin as a carrier orstructure-forming agent. Typically, gelatin is used to give sufficientstrength to the dosage form to prevent breakage during removal frompackaging, but once placed in the mouth, the gelatin allows immediatedissolution of the dosage form. Alternatively, various starches are usedto the same effect.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, thecompound of the invention is conveniently delivered in the form of asolution or suspension from a pump spray container that is squeezed orpumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made e.g. from gelatin) for use in aninhaler or insulator may be formulated containing a powder mix of acompound of the invention and a suitable powder base such as lactose orstarch.

Aerosol formulations for treatment of the conditions referred to above(e.g. migraine) in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains about 20 mg toabout 1000 mg of the compound of the invention. The overall daily dosewith an aerosol will be within the range of about 100 mg to about 10 mg.Administration may be several times daily, e.g. 2, 3, 4 or 8 times,giving for example, 1, 2 or 3 doses each time.

A proposed daily dose of the compound of the invention for oral,parenteral, rectal or buccal administration to the average adult humanfor the treatment of the conditions referred to above is from about 0.01mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of theactive ingredient of formula I per unit dose which could beadministered, for example, 1 to 4 times per day.

Assay methods are available to screen a substance for inhibition ofcyclic nucleotide hydrolysis by the PDE 10 and the PDEs from other genefamilies. The cyclic nucleotide substrate concentration used in theassay is 1/3 of the K_(m) concentration, allowing for comparisons ofIC₅₀ values across the different enzymes. PDE activity is measured usinga Scintillation Proximity Assay (SPA)-based method as previouslydescribed (Fawcett et al., 2000). The effect of PDE inhibitors isdetermined by assaying a fixed amount of enzyme (PDEs 1-11) in thepresence of varying substance concentrations and low substrate, suchthat the IC₅₀ approximates the K_(i) (cGMP or cAMP in a 3:1 ratiounlabelled to [³H]-labeled at a concentration of 1/3 Km). ). The finalassay volume is made up to 100 μl with assay buffer [50 mM Tris-HCl pH7.5, 8.3 mM MgCl₂, 1 mg/ml bovine serum albumin]. Reactions areinitiated with enzyme, incubated for 30-60 min at 30° C. to give <30%substrate turnover and terminated with 50 μl yttrium silicate SPA beads(Amersham) (containing 3 mM of the respective unlabelled cyclicnucleotide for PDEs 9 and 11). Plates are re-sealed and shaken for 20min, after which the beads were allowed to settle for 30 minutes in thedark and then counted on a TopCount plate reader (Packard, Meriden,Conn.). Radioactivity units can be converted to percent activity of anuninhibited control (100%), plotted against inhibitor concentration andinhibitor IC₅₀ values can be obtained using the “Fit Curve” MicrosoftExcel extension.

Using such assay, compounds of the present invention were determined tohave an IC₅₀ for inhibiting PDE10 activity of less than about 10micromolar.

This invention also pertains to the preparation of compounds of formulaI. The present invention also provides for methods for the synthesiscompounds of formula I. For example, the present invention provides fora process for forming the compound of formula I, comprising a step ofreacting a compound of formula II

with dimethoxymethyl-dimethyl amine and hydrazine or substitutedhydrazine (e.g., such as R₂₀—NHNH₂ where R₂₀ is alkyl).

The present invention also provides for a process for forming thecompound of formula I, comprising a step of reacting a compound offormula III

with dimethyl oxalate and a hydrazine of formula HET²-NHNH₂.

The present invention also provides for a process for forming thecompound of formula I, comprising a step of reacting a compound offormula IV

with dimethoxymethyl-dimethyl amine and hydrazine or substitutedhydrazine.

The present invention also provides for a process for forming thecompound of formula I, comprising a step of reacting a compound offormula V

with a compound of formula VI

wherein Q is a hydroxyl or a halide.

DETAILED DESCRIPTION OF THE INVENTION

Scheme 1 depicts the preparation of the pyrazole class of compounds ofthis invention. Alkylation of a substituted phenol with 2-methyl chloroquinoline provides the desired ether. Hydrolysis of the ester andtreatment with thionyl chloride provides the desired acid chloride.Addition of O,N-dimethyl hydroxyl amine hydrochloride provides theWeinreb amide for coupling (Weinreb et al, Tet Lett., 1981, 22(39)3815). Anion generation with 4-picoline and LDA followed by addition ofthe Weinreb amide affords the ketone. The ketone can then be treatedwith dimethoxymethyl-dimethyl amine at reflux to form the enaminoneintermediate. Treatment with various hydrazines affords the pyrazoleanalogues. A variety of ratios of the two isomers were obtained. Theseisomers were separated via, crystallization, Biotage MPLC, preparativeTLC or preparative HPLC. This reaction scheme is general for a varietyof starting substituted phenols, substituted quinolines and substitutedhydrazines.

Alternatively, the substituted pyrazole compounds can be prepared byalkylation of the NH pyrazole. One set of conditions is the utilizationof cesium carbonate as the base with an alkyl halide as the electrophilein a solvent such as dimethyl formamide. Some reactions require heating.

As depicted in Scheme 3, a variety of heterocycles can be prepared fromthe enaminone intermediate. Pyrimidines can be prepared by heating withsubstituted formamides in the presence of ethanol and sodium ethoxide.Isoxazoles are prepared by heating the enaminone with hydroxyl amine inmethanol/acetic acid. Only one isomer in the isoxazole case is formed.By heating with amino pyroles, amino imidazoles or amino triazoles, 6-5bicyclic systems can be formed.

A variety of 4-pyridyl heterocyclic replacements can be preparedaccording to scheme 4. Methyl heterocycles such as 3,5-dimethylisoxazole and methyl pyridazine can be deprotated with lithiumdiisopropyl amide and added to a Weinreb amide (Weinreb et al, TetLett., 1981, 22(39) 3815) to provide the desired ketone. Sequentialtreatment with dimethoxymethyl-dimethyl amine and a hydrazine providesthe heterocyclic pyrazoles. Pyrimidines and isoxazoles can also beprepared as described in Scheme 3.

N-pyridyl pyrazoles can be prepared according to Scheme 5. The startingketones are prepared by alkylation of the phenol as depicted inScheme 1. Treatment of the ketone with dimethoxymethyl-dimethyl aminefollowed by addition of 4-pyridyl hydrazine (see J. Med. Chem. 2002,45(24) 5397) provides the desired compounds. Other heterocyclicreplacements for 4-pyridyl can be prepared by using the requisitehydrazine.

As depicted in Scheme 6, 3-substituted-N-pyridyl pyrazoles can beprepared by literature methods. (see J. Med. Chem. 2004, 47, 2180).Treatment of the acetophenone (prepared according to scheme 1) withsodium methoxide and dimethyl oxalate provides the ester intermediate.Addition of 4-pyridyl hydrazine (see J. Med. Chem. 2002, 45(24) 5397)provides the pyrazole with an ester at the 3-position. This ester can beconverted to amides by hydrolysis and coupling with amines. It can beconverted to ethers by reduction to the alcohol and alkylation. Amineformation is capable by amide formation followed by reduction orconversion to the aldehyde followed by reductive amination. All of thesetransformations can be carried out by those skilled in the art oforganic chemistry.

The benzyl intermediates can be prepared by the method shown inscheme 1. The benzyl ether can be removed via treatment with hydrogengas over a palladium catalyst such as palladium on carbon or palladiumhydroxide in a variety of solvents. The phenol can then be alkylatedusing a benzylic chloride in acetone heating with potassium carbonate.Also Mitsunobu chemistry (Hughes, D. L., The Mitsunobu Reaction. OrganicReactions. Vol. 42. 1992, New York. 335-656.) can be applied to couplethe phenol with alcohols.

Many benzylic halides or alcohols are commericially available or areknown in the literature. General ways to make these intermediates bythose skilled in the art are reduction of an ester, acid or aldehyde toform an alcohol. One general procedure is the oxidation of a benylicsite with selenium dioxide to provide an aldehyde that issubsequentially reduced with sodium borohydride. Benzylic halide can beformed vial halogenation (see Syn. Comm. 1995, 25(21) 3427-3434).

Triazole analogues can be prepared in many ways. One way is depicted inScheme 9. Treatment of a hydrazide with dimethyl formamide dimethylacetal to form an intermediate, which is subsequently treated with anamine or aniline with the addition of heat and acetic acid provides the1,2,4 triazoles (see Org. Lett, 2004, 6(17), 2969-2971). Theregioisomeric triazoles can be prepared by interchanging thefunctionality of the starting materials.

Other triazole isomers can be prepared according to scheme 10 bystarting with the carboxyamides and treating with dimethyl formamidedimethyl acetal followed by the addition of aromatic hydrazines. Theregioisomeric triazoles can be prepared by interchanging thefunctionality of the starting materials.

The inverted ketone isomer can be prepared according to Scheme 11.(Bunting et al. JACS, 1988, 110, 4008.) The starting aldehyde is coupledwith a phosphonate to provide the enaminone. The enaminone is hydrolyzedto provide the desired ketone. The ketone can then be utilized accordingto Scheme 1,2 and 3 to provide the desired compounds

Scheme 12 depicts a method for synthesizing a 4,5-diaryl oxazole. In theillustrated case, 4-benzyloxy-benzaldehyde and 4-methylbenzenesulfinicacid are heated with formamide to generate a substituted formamide asshown. This transformation is known in the literature. [J. Med Chem.,2002, 45, 1697] Dehydration of the formamide in a reaction mediated byPOCl3 gives a tosylmethyl isocyanate. This class of compound can betreated with an aldehyde and a base to yield an oxazole. In theillustrated case, the tosylmethylisocyanate is treated withisonicotinaldehyde and potassium carbonate. The product of this reactionis an oxazole possessing a 4-benzyloxyphenyl group at the 4-position ofthe oxazole ring, and a 4-pyridyl substituent at the 5-position. Thesesubstituents can be substituted with other aryl groups simply byutilizing different aryl-aldehydes for steps one and three of thesequence. Cleavage of the benzyloxy group is achieved by the standardmethod of catalytic hydrogenation, and the resultant phenol is easilyalkylated by treatment with an alkyl halide, such as2-(chloromethyl)quinoline, and cesium fluoride in DMF. The method is notlimited to the illustrated case as the relative positions of the phenyland pyridyl rings can be switched, and said rings may comprise a varietyof aryl groups displaying various substitution patterns.

Scheme 13 depicts a method for preparing 4,5-substituted oxazolespossessing alkyl group substitution in the 2-position of the oxazolering. In the illustrated case,1-(4-Benzyloxy-phenyl)-2-pyridin-4-yl-ethanone is brominated bytreatment with bromine in acetic acid according to traditional methods.The resultant α-bromoketone is then treated with ammonium acetate andsodium acetate in acetic acid, which yields the methyl-substitutedoxazole ring as disclosed in the patent literature (WO 9513067). Themethyl group can be replaced by other alkyl groups. For example,substitution of ammonium ethanoate, sodium ethanoate, and ethanoic acidacid would yield ethyl group substitution. Cleavage of the benzyloxygroup is achieved by the standard method of catalytic hydrogenation, andthe resultant phenol is easily alkylated by treatment with an alkylhalide as described above. The method is not limited to the illustratedcase as the relative positions of the phenyl and pyridyl rings can beswitched, and said rings may comprise a variety of aryl groupsdisplaying various substitution patterns.

Step 1 of Scheme 14 is an imine formation/heterocycle formation. Acompound of formula 2A wherein R1 is alkyl, benzyl, or allyl, iscondensed with 4-pyridine carboxaldehyde in solvent such as toluene andis heated to reflux with a Dean-Stark apparatus attached to remove waterfor about 40 hours. After removal of toluene, the crude imine is mixedwith tosylmethylisocyanide and a base such as potassium carbonate, in asolvent mixture of 1,2-dimethoxyethane and methanol, and is heated atreflux for about 3 hours to afford 3A.

Step 2 of Scheme 14 is a phenol dealkylation. If R1 is methyl, thedealkylation can be effected with boron tribromide (BBr3) in anon-coordinating solvent such as methylene chloride at about 20-40° C.for about 3-48 hours, where about 24 hours is preferred to yield 4A. IfR2 is benzyl, the dealkylation can be effected with in neattrifluoracetic acid with anisole at a temperature of about 75° C. forabout 3-48 hours, where about 24 hours is preferred to yield 4A. If R1is allyl, the dealkylation can be effected with a palladium catalyst,such as dichloropalladium bis(triphenylphosphine) of palladium acetate,where dichloropalladium bis(triphenylphosphine) is preferred, with areducing agent such as n-butylammonium formate, in a solvent such astetrahydrofuran, 1,2-dichloroethane, methylene chloride, or an alkanol,where 1,2-dichloroethane is preferred, in a temperature range from about20° C. to 75° C., to yield 4A.

Step 3 of Scheme 14 is a phenol alkylation. Treatment of 4A with a basesuch as potassium carbonate, sodium carbonate, cesium carbonate, sodiumhydride, or potassium hydride, where cesium carbonate or sodium hydrideare preferred, in a solvent such as tetrahydrofuran,1,2-dimethoxyethane, N,N-dimethylformamide, dimethylacetamide,N-methylpyrrolidinone, or dimethylsulfoxide, where dimethylsulfoxide orN,N-dimethylformamide are preferred, at a temperature from about 20° C.to 70° C., where about 23° C. is preferred, for about 3-48 hours, whereabout 24 hours is preferred, affords 1A.

Step 4 of Scheme 14 is an imidazole deprotonation/electrophilictrapping. Treatment of 3A with a base such as lithium diisopropyl amideor lithium 2,2,6,6-tetramethylpiperidine, where lithium diisopropylamideis preferred, in a solvent such as tetrahydrofuran, at a temperaturefrom about −78° C. to 0° C., where about −20° C. is preferred, for about5 minutes to 30 minutes, where about 10 minutes is preferred, followedby addition of the desired electrophile R3-1, affords 3B.

Step 5 of Scheme 14 is a phenol dealkylation and uses the same methodsas described for Step 2 above to produce 4B.

Step 6 of Scheme 14 is a phenol alkylation and uses the same methods asdescribed for Step 3 above to produce 1B.

Step 1 of Scheme 15 is an acylation of an amine to form an amide.Compound 2A, wherein R1 can be methyl, benzyl, or allyl, is treated withan acid chloride or a carboxylic acid in the presence of a couplingreagent, such as tri-n-propylphosphonic anhydride or dicyclohexylcarbodiimide, where tri-n-propylphosphonic anhydride is preferred, inthe presence of a base such as sodium hydroxide, potassium or sodiumcarbonate, triethylamine, or diisopropylethylamine, wherediisopropylethylamine is preferred, in a solvent system such aswater/methylene chloride, water/ethyl acetate, ethyl acetate,tetrahydrofuran, or methylene chloride, where ethyl acetate ispreferred, at a temperature from about 0° C. to 50° C., where about 20°C. to 30° C. is preferred, to yield 5A.

Step 2 consists of a chlorination to form an iminochloride, reactionwith an amine to form an amidine, followed by treatment with acid toform an imidazole. Compound 5A is treated with a chlorinating agent suchas PCl₅/POCl₃ at a temperature of about 120° C. for about 4 hours. Thechlorinating agent is removed in vacuo and an excess of1,1-diethoxy-2-ethylamine in a solvent such as isopropanol is added andthe mixture is stirred for about 5-24 hours at about 23° C. The solventis removed in vacuo and concentrated hydrochloric acid and isopropanolis added and the mixture is heated to about 90° C. for about 24 hours toyield 6A.

Step 3 of Scheme 15 is a phenol dealkylation. If R1 is methyl, thedealkylation can be effected with boron tribromide (BBr3) in anon-coordinating solvent such as methylene chloride at about 20-40° C.for about 3-48 hours, where about 24 hours is preferred to yield 7A. IfR2 is benzyl, the dealkylation can be effected with in neattrifluoracetic acid with anisole at a temperature of about 75° C. forabout 3-48 hours, where about 24 hours is preferred to yield 7A. If R1is allyl, the dealkylation can be effected with a palladium catalyst,such as dichloropalladium bis(triphenylphosphine) of palladium acetate,where dichloropalladium bis(triphenylphosphine) is preferred, with areducing agent such as n-butylammonium formate, in a solvent such astetrahydrofuran, 1,2-dichloroethane, methylene chloride, or an alkanol,where 1,2-dichloroethane is preferred, in a temperature range from about20° C. to 75° C., to yield 7A.

Step 4 of Scheme 15 is a phenol alkylation. Treatment of 7A with a basesuch as potassium carbonate, sodium carbonate, cesium carbonate, sodiumhydride, or potassium hydride, where cesium carbonate is preferred, in asolvent such as tetrahydrofuran, 1,2-dimethoxyethane,N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, ordimethylsulfoxide, where dimethylsulfoxide is preferred, at atemperature from about 20° C. to 70° C., where about 23° C. ispreferred, for about 3-48 hours, where about 24 hours is preferred,affords 1C.

The quinolyl benzaldehyde can be coupled with the ketone in the presenceof refluxing piperidine to provide the desired olefin. Treatment withhydrazine affords the NH-pyrazole. This can be further elaborated bytreatment with sodium hydride and an electrophile such as methyl iodideto provide substituted pyrazoles.

As depicted in scheme 17, the alkyne and iodide can be coupled via aSonagashira coupling and the methyl ether deprotected with borontribromide in dichloromethane. Alkylation of the phenol with2-chloromethylquinoline according to the methods described aboveprovides the penultimate intermediate. Treatment with trimethyl silylazide in a sealed tube at 70-190° C., preferably about 150° C., for24-72 h, provides the desired triazole.

General Experimental

Organic solutions were dried with magnesium or sodium sulfate if nototherwise specified. Room temperature is abbreviated as RT. HPLC-MSsystem 1 consisted of Zorbax Bonus-RP™ 4.6×150 mm column, 1.0 mL/min,solvent A=MeCN, solvent B=0.1% aqueous formic acid, linear gradient of1:9 A:B to 95:5 A:B over 10 min, using a Hewlett-Packard 1100 HPLCsystem equipped with diode array and mass detectors. HPLC system 2 useda linear gradient of 3:7 A:B to 95:5 A:B over 15 min. When purificationby RP-HPLC is indicated, a Shimadzu preparative HPLC instrument equippedwith X-Terra™ 50×50 mm column, solvent A=acetonitrile, solvent B=water,each containing either 0.1% trifluoroacetic acid (“acidic conditions”)or 0.1% concentrated ammonium hydroxide (“basic conditions”), lineargradient of 25%-85% A:B over 10 min.

The following Examples illustrate the present invention. It is to beunderstood, however, that the invention, as fully described herein andas recited in the claims, is not intended to be limited by the detailsof the following Examples.

Experimental Procedures

Preparation 1

4-(Quinolin-2-ylmethoxy)-benzoic acid methyl ester

To a solution of 2-Chloromethyl quinoline. (2 g, 9.3 mmole) in acetone(47 ml, 0.2M) was added 4-hydroxy benzoic acid methyl ester (1.42 g, 1.0eq.) and potassium carbonate (3.86 g, 3 eq.). The reaction mixture washeated at 60° C. for 16 h under N₂ atmosphere, cooled to ambienttemperature and poured into 1N sodium hydroxide (50 ml)/ethyl acetate(100 ml). The layers were separated and the organic layer driedmagnesium sulfate, filtered and concentrated. Biotage MPLC was run usinga 5-30% ethyl acetate/hexane gradient on a 40 M column to provide thetitle compound as a white solid (1.66 g, 61%). ¹H NMR (400 MHz, CDCl₃) δ8.18 (d, J=8.7 Hz, 1 H), 8.07 (d, J=8.3 Hz, 1 H), 7.95 (M, 2H), 7.82 (d,J=7.9 Hz, 1 H), 7.74 (dt, J=7.1, 1.7 Hz, 1 H), 7.62 (d, J=8.3 Hz, 1 H),7.55 (dt, J=7.9, 1.2 Hz, 1 H), 7.03 (d, J=9.1, 2 H), 5.41 (s, 2 H), 3.84(s, 3 H); MS: (M⁺H m/z=294.2).

Preparation 2

4-(Quinolin-2-ylmethoxy)-benzoic acid

To a solution of 4-(Quinolin-2-ylmethoxy)-benzoic acid methyl ester (500mg, 1.7 mmole) in tetrahydrofuran (8.5 ml) and methanol (3 ml) was added1N NaOH (3.4 ml, 2 eq.). The reaction mixture was stirred at ambienttemperature for 16 h. To the reaction mixture was added 50 ml of brineand the pH was adjusted to 3 with 1N HCl to provide a white precipitatewhich was filtered and dried to provide the title compound as a whitesolid (463 mg, 98%). ¹H NMR (400 MHz, DMSO) δ 8.39 (d, J=8.3 Hz, 1 H),7.99 (m, 2 H), 7.81 (M, 2H), 7.76 (dt, J=8.3, 1.7 Hz, 1 H), 7.64 (d,J=8.3 Hz, 1 H), 7.60 (dt, J=7.9, 1.3 Hz, 1 H), 7.12 (M, 2 H), 5.41 (s, 2H); MS: (M⁺H m/z=280.2).

Preparation 3

N-Methoxy-N-methyl4-(quinolin-2-ylmethoxy)-benzamide

To a solution of 4-(Quinolin-2-ylmethoxy)-benzoic acid (25.98 g, 93mmole) was added 250 ml of thionyl chloride under N₂. The reactionmixture stirred 3 h and the excess thionyl chloride was removed undervacuum. The acid chloride was dissolved in tetrahydrofuran (450 ml) andtriethylamine (50 ml, 4 eq.) was slowly added. O,N-dimethyl hydroxylamine hydrochloride (27 g, 3 eq.) was added and the reaction stirred 18h. The reaction mixture was placed on a rotovap to remove the solvent,partitioned between 1N NaOH and methylene chloride, separated, driedmagnesium sulfate, filtered and concentrated. The crude product wasfiltered through silica gel eluting with 30-70% ethyl acetate/hexane toproved the title compound as a brown oil (26.26 g, 87%); ¹H NMR (400MHz, CDCl₃) δ 8.17 (d, J=8.7 Hz, 1 H), 8.06 (d, J=8.3 Hz, 1 H), 7.81 (d,J=8.3 Hz, 1H), 7.67 (m, 3 H), 7.63 (d, J=8.3 Hz, 1 H), 7.52 (m, 1 H),7.01 (M, 2 H), 5.39 (s, 2 H), 3.52 (s, 3 H) 3.31 (s, 2H); MS: (M⁺Hm/z=323.2).

Preparation 4

2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone

To a solution of Lithium diisopropyl amide (1.0M) in tetrahydrofuran wasadded 4-picoline dropwise (7.55 ml, 5 eq.) at 0° C. under N₂. After 30min the anion was cooled to −78° C. In a separate round bottom flaskN-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide (5.0, 15.5 mmole)was dissolved in tetrahydrofuran (77 ml, 0.2M) and cooled to −78° C.under N₂. 1.2 eq. of the 4-picoline anion was added dropwise to theamide solution. After 45 min, 1 eq. more of the 4-picoline anion wasadded. After an addition 30 min, acetic acid (40 ml) was added dropwiseand the reaction was slowly warmed to ambient temperature. The solidproduct (acetate salt) was filtered and partitioned between saturatedsodium bicarbonate and dichloromethane. The layers were separated, driedmagnesium sulfate filtered and concentrated to provide the titlecompound as a tan solid (4.41 g, 80%). ¹H NMR (400 MHz, CDCl₃) δ 8.52(d, J=5.8 Hz, 2 H), 8.19 (d, J=8.7 Hz, 1 H), 8.07 (d, J=8.7 Hz, 1H),7.93 (m, 2 H), 7.82 (d, J=8.3 Hz, 1 H), 7.75 (m, 1 H), 7.61 (d, J=8.3Hz, 1 H), 7.54 (dt, J=7.9, 1.0 Hz, 1 H), 7.23 (m, 2 H) 7.07 (m, 2H),5.42 (s, 2H), 4.19 (s, 2H); MS: (M⁺H m/z=355.2).

Preparation 5

3-Dimethylamino-2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl}-propenone

To 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone (4.0 g,11.3 mmole) was added dimethoxymethyl-dimethyl amine (10 ml) and thereaction mixture was heated at reflux for 1 hr. Concentrated to give aquantitative yield of the title compound which was used as is in thenext step. LC/MS: RT=1.4 min, MS: (M⁺H m/z=410.2).

EXAMPLE 12-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline

To a solution of3-Dimethylamino-2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl}-propenone(9.57 g, 27 mmole) in methanol was added hydrazine hydrate (3.33 g, 40.5mmole) and the reaction mixture was heated at reflux for 1 h. Thesolvent was evaporated to yield a white solid. The solid was washed withwater and ethyl ether. The solid was recystallized from hotethanol/ethylacetate (10 ml/g) to give 8.34 g of the title compound(82%). ¹H NMR (400 MHz, DMSO) δ 8.41 (m, 3 H), 8.16 (s, 1 H), 7.97 (m,2H), 7.86 (s, 1 H), 7.75 (t, J=7.9 Hz, 1 H), 7.68 (d, J=8.3 Hz, 1 H),7.60 (t, J=7.5 Hz, 1 H), 7.33 (m, 2 H), 7.18 (m, 2 H) 7.15 (d, J=8.3 Hz,1H), 7.06 (d, J=8.3 Hz, 1H), 5.38 (s, 2H); MS: (M⁺H m/z=379.2).

EXAMPLE 22-[4-(2-Methyl-4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline

To a solution of2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline (1.72 g)in ethanol (20 ml) was added methyl hydrazine (3.5 ml, 1.5 eq.) andconcentrated sulfuric acid (0.1 ml). The reaction mixture was stirred 1h at ambient temperature and solvent evaporated. The reaction mixturewas partitioned between methylene chloride and saturated sodiumbicarbonate. The layers were separated and the organic layer driedmagnesium sulfate, filtered and concentrated. Preparative HPLCchromatography provided the title compound (minor isomer) as a whitesolid (0.30 g, 17%). ¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J=5.4 Hz, 2 H),8.21 (d, J=8.7 Hz, 1 H), 7.80 (d, J=8.3 Hz, 1H), 7.77 (s, 1 H), 7.66 (m,3 H), 7.53 (m, 1H), 7.19 (d, J=8.7 Hz, 2 H), 7.11 (d, J=8.7 Hz, 2H),7.01 (d, J=6.2 Hz, 2H) 5.40 (s, 2H), 3.69 (s, 3H); MS: (M⁺H m/z=393.3).

EXAMPLE 32-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline

To a solution of2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline (1.72 g)in ethanol (20 ml) was added methyl hydrazine (3.5 ml, 1.5 eq.) andconcentrated sulfuric acid (0.1 ml). The reaction mixture was stirred 1h at ambient temperature and solvent evaporated. The reaction mixturewas partitioned between methylene chloride and saturated sodiumbicarbonate. The layers were separated and the organic layer driedmagnesium sulfate, filtered and concentrated. Preparative HPLCchromatography provided the title compound (major isomer) as a clear oil(0.97 g, 56%). ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=5.0 Hz, 2 H), 8.17(d, J=8.7 Hz, 1 H), 8.05 (d, J=8.3 Hz, 1H), 7.81 (d, J=7.9 Hz, 1 H),7.70 (m, 1 H), 7.66 (d, J=8.7 Hz, 1H), 7.54 (s, 1H), 7.53 (m, 1H), 7.37(d, J=8.7 Hz, 2H) 7.15 (d, J=5.0, 2H), 7.00 (d, J=8.7 Hz, 2H), 5.38 (s,2H), 3.93 (s, 3H); MS: (M⁺H m/z=393.3).

EXAMPLE 42-[4-(2-Ethyl-4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting ethyl hydrazine provided the title compound. ¹H NMR(400 MHz, CDCl₃) δ 8.35 (bs, 2H), 8.23 (d, J=8.3 Hz, 1 H), 8.08 (d,J=8.3 Hz, 1 H), 7.85 (d, J=7.4 Hz, 1H), 7.83 (s, 1 H), 7.74 (m, 2 H),7.57 (t, J=7.9 Hz, 1H), 7.21 (d, J=8.7 Hz, 2 H), 7.14 (d, J=9.1 Hz, 2H), 7.04 (m, 2H) 5.42 (s, 2H), 4.03 (q, J=7.5 Hz, 2H), 1.36 (t, J=7.5Hz, 3H); MS: (M⁺H m/z=407.3).

EXAMPLE 52-[4-(1-Ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting ethyl hydrazine provided the title compound. ¹H NMR(400 MHz, CDCl₃) δ 8.35 (bs, 2H), 8.19 (d, J=8.3 Hz, 1 H), 8.07 (d,J=9.1 Hz, 1 H), 7.82 (d, J=7.9 Hz, 1H), 7.73 (t, J=8.3 Hz, 1H), 7.67 (d,J=8.3 Hz, 2 H), 7.62 (s, 1H), 7.55 (t, J=7.9 Hz, 1 H), 7.37 (d, J=9.1Hz, 2H), 7.21 (bs, 2 H), 7.01 (d, J=8.7 Hz, 2H) 5.39 (s, 2H), 4.24 (q,J=7.5 Hz, 2H), 1.56 (t, J=7.5 Hz, 3H); MS: (M⁺H m/z=407.3).

EXAMPLE 6Dimethyl-(2-{4-pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-ethyl)-amine

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting (2-hydrazino-ethyl)-dimethyl-amine provided the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 8.44 (dd, J=4.6, 1.7, Hz, 2 H), 8.18(d, J=8.3 Hz, 1 H), 8.06 (d, J=8.3 Hz, 1H), 7.82 (d, J=8.7 Hz, 1 H),7.71 (m 2H), 7.55 (t, J=7.1 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 7.15 (d,J=6.2 Hz, 2H) 7.00 (d, J=8.7 Hz, 2H), 5.38 (s, 2H), 4.25 (t, J=6.6 Hz,2H), 2.82 (t, J=6.6 Hz, 2H), 2.28 (s, 6H); MS: (M⁺H m/z=450.4).

EXAMPLE 7Dimethyl-(2-{4-pyridin-4-yl-5-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-ethyl)-amine

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting (2-hydrazino-ethyl)-dimethyl-amine provided the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (d, J=6.2 Hz, 2 H), 8.22 (d,J=8.3 Hz, 1 H), 8.08 (d, J=8.7 Hz, 1H), 7.85 (m, 2 H), 7.73 (m 2H), 7.57(t, J=7.1 Hz, 1H), 7.23 (m, 2H), 7.17 (d, J=9.1 Hz, 2H) 7.00 (d, J=6.2Hz, 2H), 5.42 (s, 2H), 4.05 (t, J=6.6 Hz, 2H), 2.66 (t, J=7.1 Hz, 2H),2.10 (s, 6H); MS: (M⁺H m/z=450.4).

EXAMPLE 82-{4-[-Pyridin4-yl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazol-3-yl]-phenoxymethyl}-quinoline

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting (2,2,2-trifluoro-ethyl)-hydrazine provided the titlecompound. MS: (M⁺H m/z=461.2).

EXAMPLE 92-{4-[-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline

To a solution of2-[4-(4-Pyridin4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline (26.5 g)in dimethyl formamide (140 mL) was added 1,1,1-Trifluoro-2-iodo-ethane(21 mL, 2.0 eq.) and cesium carbonate (68.3 g, 3 eq.) and the reactionmixture heated at 60° C. for 24 h. The reaction mixture was diluted withwater, extracted 3× methylene chloride, dried with magnesium sulfate,filtered and concentrated. Purification via flash chromatography elutingwith 5% methanol/70% ethyl acetate/hexanes provided the title compound20.85 g as an 8:1 regioisomeric mixture. Preparative HPLC eluting withacetonitile/methanol (98:2) on a chiralpak AD column with a flow rate of430 ml/Min provided the pure title compound as a free base 13.4 g. ¹HNMR (400 MHz, CDCl₃) δ 8.45 (m, 2 H), 8.16 (d, J=8.3 Hz, 1 H), 8.04 (d,J=8.3 Hz, 1H), 7.96 (s, 1H), 7.79 (d, J=8.3 Hz, 1 H), 7.69 (m, 1 H),7.64 (d, J=8.3 Hz, 1 H), 7.50 (m, 1H), 7.36 (d, J=8.7 Hz, 2 H), 7.14 (d,J=6.2 Hz, 2H), 6.98 (d, J=9.1 Hz, 2 H), 5.35 (s, 2H), 4.75 (q, J=8.3 Hz,2 H); MS: (M⁺H m/z=427.1).MS: (M⁺H m/z=461.2).

EXAMPLE 101-{4-Pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting 1-hydrazino-propan-2-ol provided the title compound. ¹HNMR (400 MHz, CDCl₃) δ 8.44 (bs, 2 H), 8.20 (d, J=8.3 Hz, 1 H), 8.08 (d,J=8.3 Hz, 1H), 7.83 (d, J=8.3 Hz, 1 H), 7.75 (m 2H), 7.67 (d, J=8.3 Hz,1H), 7.56 (t, J=8.3 Hz, 1H), 7.36 (d, J=8.7 Hz, 2H) 7.30 (m, 2H), 7.03(d, J=9.1 Hz, 2 H), 5.40 (s, 2H), 4.49 (m, 1H), 4.23 (m, 1H), 4.02 (m,1H), 1.83 (m, 1H), 1.28 (d, J=6.2 Hz, 3H); MS: (M⁺H m/z=437.2).

EXAMPLE 111-{4-Pyridin-4-yl-5-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting 1-hydrazino-propan-2-ol provided the title compound. ¹HNMR (400 MHz, CDCl₃) δ 8.37 (d, J=6.2 Hz, 2 H), 8.23 (d, J=8.7 Hz, 1 H),8.08 (d, J=8.3 Hz, 1H), 7.84 (m, 2 H), 7.75 (m 2H), 7.57 (t, J=6.6 Hz,1H), 7.20 (d, J=9.1 Hz, 2H), 7.13 (d, J=8.7 Hz, 2H) 7.00 (dd, J=6.2, 1.7Hz, 2H), 5.42 (s, 2H), 4.17 (m, 1H), 3.94 (m, 2H), 3.86 (m, 1H), 1.12(d, J=6.6 Hz, 3H); MS: (M⁺H m/z=437.3).

EXAMPLE 122-[4-(2-Isopropyl-4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting isopropyl hydrazine provided the title compound. ¹H NMR(400 MHz, CDCl₃) δ 8.33 (bs, 2 H), 8.24 (d, J=8.3 Hz, 1 H), 8.08 (d,J=8.3 Hz, 1H), 7.86 (s, 1H) 7.83 (m, 1 H), 7.72 (m 2H), 7.58 (t, J=7.9Hz, 1H), 7.20 (d, J=8.7 Hz, 2H), 7.15 (d, J=9.1 Hz, 2H) 7.04 (m, 2H),5.43 (s, 2H), 4.31 (m, 1H), 1.43 (d, J=6.6 Hz), 6H); MS: (M⁺Hm/z=421.2).

EXAMPLE 13 2-[4-(4-Pyridin-4yl-isoxazol-5-yl)-phenoxymethyl]-quinoline

2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone (200 mg,0.56 mmole) was heated at reflux in dimethoxymethyl-dimethyl amine (1ml) for 1 h and concentrated. The crude product was dissolved inmethanol/water (3:1, 4 ml) and hydroxyl amine hydrochloride (43 mg, 1.1eq.) was added. After 1 h, acetic acid was added (0.016 ml) and thereaction was heated at reflux for 1h. Cooled to ambient temperaturepoured into saturated sodium bicarbonate, extracted with methylenechloride, dried magnesium sulfate, filtered and concentrated. BiotageMPLC was run on a 25S column elution with 3% methanol/1% ammoniumhydroxide/ethyl acetate 50% in hexanes to provide the title compound asa tan solid (94 mg, 45%). ¹H NMR (400 MHz, CDCl₃) δ 8.59(dd, J=6.2, 1.7Hz, 2 H), 8.36 (s, 1H), 8.20 (d, J=8.3 Hz, 1H), 8.07 (d, J=8.7 Hz, 1 H),7.82 (d, J=9.1 Hz, 1H), 7.73 (dt, J=7.1, 1.7 Hz, 1H), 7.64 (d, J=8.3 Hz,1H), 7.54 (m, 3H), 7.28 (d, J=4.2 Hz, 2H) 7.05 (d, J=9.1, 2H), 5.40 (s,2H); MS: (M⁺H m/z=380.2).

EXAMPLE 14 2-[4-(5-Pyridin-4-yl-pyrimidin-4-yl)-phenoxymethyl]-quinoline

2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone (200 mg) washeated at reflux in dimethoxymethyl-dimethyl amine (1 ml) for 1 h andconcentrated. The crude reaction mixture was dissolved in ethanol (3 ml)and formamidine hydrochloride (90 mg, 2 eq.) was added. In a separateflask sodium (40 mg) was added to ethanol 3 ml and stirred 10 min. Thesodium ethoxide solution was added to the reaction mixture and washeated at reflux for 1 h. The reaction mixture was concentrated andpurified via Biotage MPLC chromatography on a 25S column eluting with40-100% ethyl acetate/hexane to provide the title compound (83 mg, 38%).¹H NMR (400 MHz, CDCl₃) δ 8.53(m, 3 H), 8.14 (d, J=8.7 Hz, 1H), 8.03 (d,J=8.3 Hz, 1H), 7.79 (d, J=7.9 Hz, 1 H), 7.70 (m, 1 H), 7.58 (d, J=8.7Hz, 1H), 7.50 (m, 1H), 7.33 (d, J=9.1 Hz, 2H) 7.10 (d, J=6.2, 2H),6.91(d, J=9.1 Hz, 2H), 5.34 (s, 2H) 2.77 (s, 3H); MS: (M⁺H m/z=391.2).

EXAMPLE 152-[4-(2-Methyl-5-pyridin-4-yl-pyrimidin-4-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[4-(5-Pyridin-4-yl-pyrimidin-4-yl)-phenoxymethyl]-quinoline butsubstituting acetamidine hydrochloride provide the title compound. ¹HNMR (400 MHz, CDCl₃) δ 9.21 (s, 1H), 8.63 (S, 1H), 8.58(m, 2 H), 8.17(d, J=8.7 Hz, 1H), 8.04 (d, J=8.7 Hz, 1H), 7.81 (d, J=8.3 Hz, 1 H), 7.70(m, 1 H), 7.60 (d, J=8.3 Hz, 1H), 7.52 (m, 1H), 7.37 (m, 2H) 7.15 (d,J=6.2, 2H), 6.93 (d, J=9.1 Hz, 2H), 5.35 (s, 2H); MS: (M⁺H m/z=405.2).

EXAMPLE 162-[4-(2-Methyl-6-pyridin-4-yl-pyrazolo[1,5-a]pyrimidin-7-yl)-phenoxymethyl]-quinoline

To a solution of3-Dimethylamino-2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl}-propenone(229 mg, 0.56 mmole) in ethanol (3 ml) was added piperidine (2 eq.) and5-methyl-2H-pyrazol-3-ylamine (108 mg, 2 eq.) and the reaction mixturewas heated at reflux for 3 h. The reaction mixture was cooled to RT,filtered and product washed with ethanol and hexane to provide the titlecompound (96 mg, 39%). ¹H NMR (400 MHz, CDCl₃) δ 8.51 (d, J=7.9 Hz, 2H),8.46 (S, 1H), 8.30(m, 1 H), 8.18 (m, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.78(m, 1 H), 7.71 (m, 1 H), 7.60 (m, 1 H), 7.41 (d, J=8.7, 2H), 7.21 (m,2H) 7.07 (d, J=8.7, 2H), 6.60 (s, 1H), 5.50 (s, 2H) 2.48 (s, 3H); MS:(M⁺H m/z=444.2).

EXAMPLE 172-[4-(2-Methyl-6-pyridin-4-yl-[1,2,4]triazolo[1.5-a]pyrimidin-7-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[4-(2-Methyl-6-pyridin-4-yl-pyrazolo[1,5-a]pyrimidin-7-yl)-phenoxymethyl]-quinolinebut substituting 5-Methyl-2H-[1,2,4]-triazol-3ylamine provided the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 8.75 (s, 1H), 8.55 (m, 2H), 8.21(d,J=8.3 Hz, 1 H), 8.06 (d, J=7.5 Hz, 1H), 7.84 (d, J=7.1 Hz, 1H), 7.73 (m,1H), 7.64 (d, J=8.3 Hz, 1 H), 7.55 (m, 1H), 7.42 (d, J=8.7, 2H), 7.08(m, 4H), 5.39 (s, 2H) 2.60 (s, 3H); MS: (M⁺H m/z=445.2).

Preparation 6

2-Pyridazin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone

Following the procedure for the preparation of2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone butsubstituting 4-methyl pyridazine for 4-picoline provided the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 9.12 (d, J=5.4 Hz, 1 H), 9.08 (d,J=8.7 Hz, 2.1 H), 8.20 (d, J=8.3 Hz, 1H), 8.07 (d, J=8.3 Hz, 1 H), 7.96(m, 2 H), 7.83 (d, J=7.9 Hz, 1 H), 7.76 (m, 1 H), 7.62 (d, J=8.3 Hz, 1H), 7.55 (m, 1 H) 7.38 (dd, J=5.4, 2.5 Hz, 1H), 7.09 (m, 2H), 5.44 (s,2H) 4.23 (s, 2H); MS: (M⁺H m/z=356.2).

Preparation 7

3-Dimethylamino-2-pyridazin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenone

Following the procedure for the preparation of3-Dimethylamino-2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl}-propenonebut substituting2-Pyridazin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone providedthe title compound. LC/MS: RT=1.8 min, MS: (M⁺H m/z=411.2).

EXAMPLE 182-[4-(4-Pyridazin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline butsubstituting3-Dimethylamino-2-pyridazin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenoneprovided the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃) δ9.11 (s, 1H), 9.01 (d, J=5.0 Hz, 1H), 8.34(d, J=8.7 Hz, 1 H), 8.25 (d,J=8.7 Hz, 1H), 7.89 (m 2H), 7.81 (d, J=8.3 Hz, 1 H), 7.79 (m, 2 H), 7.61(t, J=7.6 Hz, 1H), 7.34 (m, 1H), 7.31 (d, J=8.7 Hz, 2H), 7.05 (d, J=8.7,2H), 5.49 (s, 2H); MS: (M⁺H m/z=380.2).

EXAMPLE 192-[4-(1-Methyl-4-pyridazin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting3-Dimethylamino-2-pyridazin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenoneprovided the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃) δ9.11 (d, J=2.5 Hz, 1H), 8.96 (d, J=5.4 Hz, 1H), 8.19(d, J=8.7 Hz, 1H),8.06 (d, J=8.3 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.73 (t, J=7.1 Hz, 1 H),7.67 (m, 2H), 7.55 (t, J=7.1 Hz, 1H), 7.34 (d, J=9.1 Hz, 2H), 7.24 (m,1H), 7.02 (d, J=6.6 Hz, 2H), 5.39 (s, 2H) 3.97 (s, 3H); MS: (M⁺Hm/z=394.2).

EXAMPLE 202-[4-(2-Methyl-4-pyridazin4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting3-Dimethylamino-2-pyridazin4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenoneprovided the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃) δ8.99 (d, J=2.5 Hz, 1H), 8.90 (d, J=5.4 Hz, 1H), 8.24(d, J=8.7 Hz, 1H),8.08 (d, J=8.7 Hz, 1H), 7.89 (s, 1H), 7.85 (d, J=8.3 Hz, 1 H), 7.75 (t,J=7. 1 Hz, 1 H), 7.70 (d, J=8.3 Hz, 1H), 7.57 (t, J=7.1 Hz, 1H), 7.21(d, J=8.7 Hz, 2H), 7.15 (d, J=9.1 Hz, 2H), 7.11 (m, 1 H), 5.43 (s, 2H)3.73 (s, 3H); MS: (M⁺H m/z=394.2).

EXAMPLE 212-[-4-(4-Pyrimidin-4yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline andmaking the necessary chemical substitutions provided the title compoundas a white solid. LC/MS: RT=1.8 min, MS: (M⁺H m/z=380.2).

EXAMPLE 222-[4-(4-Pyridazin-3-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline andmaking the necessary chemical substitutions provided the title compoundas a white solid. LC/MS: RT=1.7 min, MS: (M⁺H m/z=380.2).

Preparation 8

2-(3-Methyl-isoxazol-5-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone

Following the procedure for the preparation of2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone butsubstituting 3,5-dimethyl isoxazole for 4-picoline provided the titlecompound. LC/MS: RT=2.3 min, MS: (M⁺H m/z=359.2).

Preparation 9

3-Dimethylamino-2-(3-methyl-isoxazol-5-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenone

Following the procedure for the preparation of3-Dimethylamino-2-pyridin4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl}-propenonebut2-(3-Methyl-isoxazol-5-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanoneprovided the title compound. LC/MS: RT=2.1 min, MS: (M⁺H m/z=414.2).

EXAMPLE 232-{4-[4-(3-Methyl-isoxazol-5-yl)-2H-pyrazol-3-yl]-phenoxymethyl}-quinoline

Following the procedure for the preparation of2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline butsubstituting3-Dimethylamino-2-(3-methyl-isoxazol-5-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenoneprovided the title compound. ¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J=8.7Hz, 1H), 8.12 (d, J=8.7 Hz, 1H), 7.94(s, 1 H), 7.84 (d, J=7.1 Hz, 1H),7.74 (m, 1H), 7.69 (d, J=8.3 Hz, 1 H), 7.57 (t, J=6.6 Hz, 2 H), 7.46 (d,J=8.87 Hz, 2H), 7.08 (d, J=8.7 Hz, 2H), 5.88 (s, 1H), 5.42 (s, 2H), 2.23(s, 3H); MS: (M⁺H m/z=383.2).

EXAMPLE 242-{4-[2-Methyl-4-(3-methyl-isoxazol-5-yl)-2H-pyrazol-3-yl]-phenoxymethyl)-quinoline

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting3-Dimethylamino-2-(3-methyl-isoxazol-5-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenoneprovided the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃) δ8.25 (d, J=8.7 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.89(s, 1 H), 7.85 (d,J=8.3 Hz, 1H), 7.74 (m, 2H), 7.57 (t, J=7.1 Hz, 1 H), 7.28 (s, 1 H),7.26 (d, J=10.4 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 5.45 (s, 2H), 3.71 (s,3H), 2.16 (s, 3H); MS: (M⁺H m/z=397.2).

EXAMPLE 252-{4-[1-Methyl-4-(3-methyl-isoxazol-5-yl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting3-Dimethylamino-2-(3-methyl-isoxazol-5-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenoneprovided the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃) δ8.18 (d, J=8.3 Hz, 1H), 8.07 (d, J=8.7 Hz, 1H), 7.81(d, J=7.1 Hz, 1 H),7.77 (s, 1H), 7.74 (t, J=7.1 Hz, 1H), 7.67 (d, J=8.7 Hz, 1 H), 7.54 (t,J=7.1 Hz, 1H), 7.48 (d, 8.7 Hz, 2 H), 7.07 (d, J=8.7 Hz, 2H), 5.81 (s,1H), 5.41 (s, 2H), 3.92 (s, 3H), 2.20 (s, 3H); MS: (M⁺H m/z=397.2).

EXAMPLE 262-{4-[2-Methyl-5-(3-methyl-isoxazol-5-yl)-pyrimidin-4-yl]-phenoxymethyl}-quinoline

Following the procedure for the preparation of2-[4-(5-Pyridin-4-yl-pyrimidin-4-yl)-phenoxymethyl]-quinoline butsubstituting acetamidine hydrochloride and3-Dimethylamino-2-(3-methyl-isoxazol-5-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenoneprovided the title compound as the hydrochloride salt. ¹H NMR (400 MHz,CDCl₃) δ 8.87 (s, 1H), 8.18 (d, J=8.3 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H),7.82(d, J=8.3 Hz, 1 H), 7.72 (t, J=7.1 Hz, 1H), 7.63 (d, J=8.7 Hz, 1H),7.53 t, J=6.6 Hz, 1 H), 7.45 (d, J=9.1 Hz, 2H), 7.05 (d, J=9.1 Hz, 2H),5.79 (s, 1H), 5.40 (s, 2H), 2.78 (s, 3H), 2.23 (s, 3H); MS: (M⁺Hm/z=409.2).

Preparation 10

1-[4-(Quinolin-2-ylmethoxy)-phenyl]-ethanone

To a solution of 2-Chloromethyl quinoline (2.5 g, 14 mmole) in acetone(47 ml) was added 4-hydroxy acetophenone (1.92 g, 1.0 eq.) and potassiumcarbonate (2.5 g, 2 eq.). The reaction mixture was heated at 60° C. for16 h under N₂ atmosphere, cooled to ambient temperature and poured into1N sodium hydroxide (50 ml)/ethyl acetate (100 ml). The layers wereseparated and the organic layer dried magnesium sulfate, filtered andconcentrated. Biotage MPLC was run using a 5-40% ethyl acetate/hexanegradient on a 40 M column to provide the title compound as a white solid(2.75 g, 71%). ¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, J=8.7 Hz, 1 H), 8.07(d, J=8.7, 1H), 7.91 (m, 2H), 7.82 (dd, J=8.3, 1.3 1H), 7.73 (t, J=7.1Hz, 1 H), 7.62 (d, J =8.3 Hz, 1 H), 7.54 (t, J=7.1 Hz, 1 H), 7.06 (m,2H), 5.42 (s, 2 H), 2.51 (s, 3 H); MS: (M⁺H m/z=278.3).

Preparation 11

3-Dimethylamino-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenone

1-[4-(Quinolin-2-ylmethoxy)-phenyl]-ethanone (1.0 g, 3.61 mmole) wasstirred in dimethoxymethyl-dimethyl amine (5 ml) and heated at refluxfor 18 h. The reaction mixture was cooled to RT and a tan precipitateformed. It was filtered and washed with ethyl ether to provide the titlecompound 840 mg, 71%). ¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, J=8.3 Hz, 1H), 7.97 (m, 2H), 7.91 (m, 2H), 7.84 (m, 2H), 7.75 (t, J=6.6 Hz, 1 H),7.62 (m, 3H), 7.05 (d, J=8.7 Hz, 2 H), 5.77 (d, J=12.0, 1H), 5.40 (s, 2H), 3.07 (bs, 3 H), 2.84 (bs, 3H); MS: (M^(+H m/z=)333.3).

EXAMPLE 272-[4-(2-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline

To a solution of3-Dimethylamino-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenone (46 mg) inethanol (0.7 ml) was added water (0.7 ml), acetic acid (0.05ml) and4-pyridyl hydrazine (25 mg, 1 eq.). The reaction mixture was heated at100° C. for 3 h, cooled to RT, poured into 1 N NaOH, extracted withchloroform, dried magnesium sulfate, filtered and concentrated. BiotageMPLC was run on a 25S column eluting with 20-80% ethyl acetate/hexane toprovide the title compound as a tan solid (31 mg, 61%). ¹H NMR (400 MHz,CDCl₃)δ 8.51 (bs, 2H), 8.24 (d, J=8.7 Hz, 1 H), 8.11 (d, J=8.7, 2H),7.84 (d, J=8.3 Hz, 1H), 7.74 (m, 2H), 7.69 (d, J=8.7 Hz, 1 H), 7.58 (t,J=7.1, 1H), 7.32 (bs, 2H), 7.19 (d, J=6.6 Hz, 2H), 7.04 (d, J=6.6, 2H),5.40 (s, 2 H), 6.45 (s, 1H), 5.42 (s, 2H); MS: (M⁺H m/z=379.2).

EXAMPLE 28 2-[4-(3-Methyl-5-pyridin-4-yl[1,2,4]triazol-4-yl)-phenoxymethyl]-quinoline

To a solution of isonicotinic hydrazide (1.04 g, 1.12 eq.) inacetonitrile (30 ml) was added N,N-dimethylacetamide dimethyl acetal(1.1 eq.) and the reaction mixture was heated at 50° C. for 3 h. Thereaction mixture was cooled to ambient temperature and concentrated.4-(Quinolin-2-ylmethoxy)-phenylamine (1.70 g) was added along withacetic acid (30 ml) and the reaction mixture was heated at reflux for 3h, and cooled to ambient temperature. The reaction mixture wasconcentrated on a rotovap and purified via combiflash MPLC to providethe title compound as a tan solid (56%). ¹H NMR (400 MHz, CDCl₃) δ 8.51(d, J=6.2 Hz, 2H), 8.24 (d, J=8.7 Hz, 1 H), 8.08 (d, J=8.7, 1H), 7.85(d, J=7.9 Hz, 1H), 7.76 (t, J=8.3 Hz, 1H), 7.67 (d, J=8.7 Hz, 1 H), 7.58(t, J=7.1, 1H), 7.29 (d, J=6.2 Hz, 2 H), 7.17 (d, J=9.1 Hz, 2H), 7.12(d, J=9.1 Hz, 2 H), 5.43 (s, 2 H), 2.31 (s, 3H); MS: (M⁺H m/z=394.3).

Preparation 12

4-benzyloxy-N-methoxy-N -methyl-benzamide

Following the procedure for the preparation ofN-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide but substituting4-benzyloxy benzoic acid provided the title compound as a waxy solid.MS: (M⁺H m/z=272.3).

Preparation 13

1-(4-Benzyloxy-phenyl)-2-pyridin-4-yl-ethanone

Following the procedure for the preparation of2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone butsubstituting 4-benzyloxy-N-methoxy-N-methyl-benzamide provided the titlecompound. MS: (M⁺H m/z=304.2).

Preparation 14

4-[3-(4-Benzyloxy-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyridine

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting 1-(4-Benzyloxy-phenyl)-2-pyridin-4-yl-ethanone providedthe title compound. MS: (M⁺H m/z=342.2).

Preparation 15

4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol

To a solution of4-[3-(4-Benzyloxy-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyridine (1.28 g) inethanol (50 ml)/ethyl acetate (50 ml) in a parr bottle was addedPalladium hydroxide (500 mg). The parr bottle was charged to 40 psi on ashaker for 6 h. The reaction mixture was filtered and concentrated. MPLCbiotage chromatography eluting with methanol (1-7%)/chloroform providedthe title compound (860 mg, 91%). ¹H NMR (400 MHz, DMSO) δ 9.53 (s, 1H),8.39 (d, J=5.8 Hz, 2 H), 7.15 (m, 4H), 6.72 (d, J=8.7 Hz, 1H), 3.84 (s,3H); MS: (M⁺H m/z=252.2).

EXAMPLE 292-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoxaline

To a solution of 4-(1-Methyl4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol (50mg) in dioxane (2 ml) was added triphenylphosphine (84 mg),quinoxaline-2-yl-methanol (48 mg) and di-t-butyl-aza-dicarboxylate (73mg) and the reaction mixture was heated at 60° C. for 18 h. The reactionmixture was poured into 1N NaOH, extracted 3× methylene chloride, driedmagnesium sulfate, filtered and concentration Purification via MPLCbiotage chromatography provided the title compound (54 mg, 67%). ¹H NMR(400 MHz, CDCl₃) δ 9.09 (s, 1H), 8.45 (d, J=6.2 Hz, 2H), 8.10 (m, 2 H),7.77 (m, 2H), 7.55 (s, 1H), 7.37 (d, J=9.1 Hz, 2H), 7.10 (d, J=6.9 Hz, 2H), 7.01 (d, J=8.7, 2H), 5.41 (s, 2 H), 3.94 (s, 3H); MS: (M⁺Hm/z=394.4).

EXAMPLE 307-Chloro-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinehydrogen chloride

Following the procedure for the preparation of4-(Quinolin-2-ylmethoxy)-benzoic acid methyl ester but substituting4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol and7-chloro-2-chloromethyl-quinoline provided the title compound. ¹H NMR(400 MHz, DMSO) δ 8.66 (d, J=6.6 Hz, 2H), 8.54 (s, 1 H), 8.47 (d, J=8.3,2H), 8.04 (m, 2H), 7.70 (m, 2H), 7.65 (m, 1H), 7.36 (d, J=8.7 Hz, 2H),7.12 (d, J=8.7, 2H), 5.38 (s, 2H), 3.90 (s, 3 H); MS: (M⁺H m/z=427.1).

EXAMPLE 316-Fluoro-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinehydrogen chloride

Following the procedure for the preparation of7-Chloro-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinehydrogen chloride but substituting 2-chloromethyl-6-fluoro-quinolineprovided the title compound. ¹H NMR (400 MHz, DMSO) δ 8.67 (d, J=6.6 Hz,2H), 8.55 (s, 1 H), 8.42 (d, J=8.3, 1H), 8.04 (m, 1H), 7.82 (m, 1H),7.71 (m, 4H), 7.36 (d, J=8.7 Hz, 2H), 7.12 (d, J=8.7, 2H), 5.37 (s, 2H),3.91 (s, 3 H); MS: (M⁺H m/z=411.2).

Preparation 16

3-Fluoro-4-(quinolin-2-ylmethoxy)-benzoic acid quinolin-2-ylmethyl ester

Following the procedure for the preparation of4-(Quinolin-2-ylmethoxy)-benzoic acid methyl ester but substituting3-fluoro-4-hydroxy-benzoic acid provided the title compound. MS: (M⁺Hm/z=439.0).

Preparation 17

3-Fluoro-4-(quinolin-Z-ylmethoxy)-benzoic acid

Following the procedure for the preparation of4-(Quinolin-2-ylmethoxy)-benzoic acid but substituting3-Fluoro-4-(quinolin-2-ylmethoxy)-benzoic acid quinolin-2-ylmethyl esterprovided the title compound. MS: (M⁺H m/z=298.2).

Preparation 18

3-Fluoro-N-methoxyl-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide

Following the procedure for the preparation ofN-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide but substituting3-Fluoro-4-(quinolin-2-ylmethoxy)-benzoic acid provided the titlecompound. MS: (M⁺H m/z=341.2).

Preparation 19

1-[3-Fluoro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanone

Following the procedure for the preparation of2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone butsubstituting3-Fluoro-N-methoxyl-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide providedthe title compound. MS: (M⁺H m/z=373.1).

EXAMPLE 322-[2-Fluoro-4-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline butsubstituting1-[3-Fluoro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanoneprovided the title compound. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (bs, 2H),8.19 (d, J=8.7 Hz, 1H), 8.05 (d, J=8.3 Hz, 1 H), 7.71 (m, 4H), 7.54 (t,J=7.1 Hz, 1H), 7.18 (m, 3H), 7.07 (m, 2 H), 5.42 (s, 2 H); MS: (M⁺Hm/z=397.0).

EXAMPLE 332-[2-Fluoro-4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting1-[3-Fluoro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanoneprovided the title compound. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J=6.2Hz, 2H), 8.21 (d, J=8.3 Hz, 1H), 8.05 (d, J=8.7 Hz, 1 H), 7.83 (d, J=7.9Hz, 2H), 7.72 (m, 2H), 7.55 (m, 2H), 7.16 (m, 2 H), 7.07 (m, 1H), 6.99(m, 2H), 5.45 (s, 2 H), 3.95 (s, 3H); MS: (M⁺H m/z=411.0).

Preparation 20

2,3-Difluoro-4-(quinolin-2-ylmethoxy)-benzoic acid quinolin-2-yl methylester

Following the procedure for the preparation of4-(Quinolin-2-ylmethoxy)-benzoic acid methyl ester but substituting2,3-difluoro-4-hydroxy-benzoic acid provided the title compound. MS:(M⁺H m/z=457.1).

Preparation 21

2,3-Difluoro-4-(quinolin-2-ylmethoxy)-benzoic-acid

Following the procedure for the preparation of4-(Quinolin-2-ylmethoxy)-benzoic acid but substituting2,3-Difluoro-4-(quinolin-2-ylmethoxy)-benzoic acid quinolin-2-yl methylester provided the title compound. MS: (M⁺H m/z=316.1).

Preparation 22

2,3-Difluoro-N-methoxy-N -methyl-4-(quinolin-2-ylmethoxy)-benzamide

Following the procedure for the preparation ofN-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide but substituting2,3-Difluoro-4-(quinolin-2-ylmethoxy)-benzoic acid provided the titlecompound. MS: (M⁺H m/z=359.1).

Preparation 23

1-[2,3-Difluoro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanone

Following the procedure for the preparation of2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone butsubstituting2,3-Difluoro-N-methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamideprovided the title compound. MS: (M⁺H m/z=391.1).

EXAMPLE 342-[2,3-Difluoro-4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting1-[2,3-Difluoro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanoneprovided the title compound. ¹H NMR (400 MHz, CDCl₃) δ 8.44 (bs, 2H),8.22 (d, J=8.7 Hz, 1H), 8.06 (d, J=8.7 Hz, 1 H), 7.84 (d, J=7.9 Hz, 1H),7.70 (m, 2 H), 7.66 (s, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.08 (m, 3H), 6.88(m, 1H), 5.48 (s, 2H); MS: (M⁺H m/z=429.1).

Preparation 24

2-Fluoro-4-(quinolin-2-ylmethoxy)-benzoic acid quinolin-2-ylmethyl ester

Following the procedure for the preparation of4-(Quinolin-2-ylmethoxy)-benzoic acid methyl ester but substituting2-fluoro-4-hydroxy-benzoic acid provided the title compound. MS: (M⁺Hm/z=439.0).

Preparation 25

2-Fluoro-4-(quinolin-2-ylmethoxy)-benzoic acid

Following the procedure for the preparation of4-(Quinolin-2-ylmethoxy)-benzoic acid but substituting2-Fluoro-4-(quinolin-2-ylmethoxy)-benzoic acid quinolin-2-yl methylester provided the title compound. MS: (M⁺H m/z=298.2).

Preparation 26

2-Fluoro-n-methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide

Following the procedure for the preparation ofN-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide but substituting2-Fluoro-4-(quinolin-2-ylmethoxy)-benzoic acid provided the titlecompound. MS: (M⁺H m/z =341.2).

Preparation 27

1-{2-Fluoro-4-(quinolin-2-ylmethoxy)-phenyl}-2-pyridin-4-yl-ethanone

Following the procedure for the preparation of2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone butsubstituting2-Fluoro-n-methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide providedthe title compound. MS: (M⁺H m/z=373.0).

EXAMPLE 352-[3-Fluoro-4-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline butsubstituting1-{2-Fluoro-4-(quinolin-2-ylmethoxy)-phenyl}-2-pyridin-4-yl-ethanoneprovided the title compound. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J=6.5Hz, 2H), 8.22 (d, J=8.3 Hz, 1H), 8.08 (d, J=8.7 Hz, 1 H), 7.84 (s, 1H),7.82 (m, 1H), 7.74 (m, 1H), 7.65 (d, J=8.7 Hz, 1 H), 7.55 (m, 1 H), 7.25(m, 1 H), 7.18 (d, J=6.2 HZ, 2H), 6.85 (d, J=10.9, 2 H), 5.38 (s, 2 H);MS: (M⁺H m/z=397.2).

Preparation 28

4-(Quinolin-2-ylmethoxy)-benzaldehyde

Following the procedure for the preparation of4-(Quinolin-2-ylmethoxy)-benzoic acid methyl ester but substituting4-Hydroxy-benzaoldehyde provided the title compound. MS: (M⁺Hm/z=264.2).

Preparation 29

1-Pyridin-4-yl-2-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone

To a solution of 4-pyridine carboxaldehyde (10.8 g) in 2-propanol (50ml) was added aniline (9.3 g). After 15 min, thephenyl-pyridin-4-ylmethylene-amine product (68%) was filtered and usedcrude. To a solution of the imine in ethoanol (35 ml) was added diphenylphosphite (13.1 ml) and stirred 1 h. Ethyl ether (200 mL) was added andthe (Phenylamino-pyridin-4-yl-methyl-phosphonic acid diphenyl ester(5.06 g) was filtered. The phophonic ester (0.98 g) in THF (25 ml) wasstirred at −40° C. under N₂. A solution of KOH/methanol (0.146 g/10%)was added followed by 4-(Quinolin-2-ylmethoxy)-benzaldehyde (0.62 g).The crude reation mixture was warmed to ambient temperature for 1 h andconcentrated. The crude product was stirred in acetonitrile (1 mL)/1 mlconc. HCl for 1 h, quenched with sat'd sodium bicarbonate, extractedwith chloroform, dried magnesium sulfate, filtered and concentrated.Purification via MPLC combiflash provided the title compound. MS: (M⁺Hm/z=355.1).

EXAMPLE 362-[4-(5-Pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline

1-Pyridin-4-yl-2-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone (168 mg) washeated in diethoxymethyl-dimethyl amine (1 ml) at reflux for 2 hours.The reaction mixture was concentrated and dissolved in methanol (1 ml)and hydrazine hydrate (0.023 ml) was added and the reaction mixture washeated at 65° C. for 1 h. The reaction mixture was concentrated andpurified by combiflash MPLC chromatography to provide the title compound(90%). ¹H NMR (400 MHz, CDCl₃) δ 8.37 (bs, 2H), 8.18 (d, J=8.7 Hz, 1 H),7.99 (d, J=8.7 Hz, 1H), 7.78 (d, J=8.3 Hz, 1 H), 7.66 (m, 2 H), 7.54 (s,1 H), 7.48 (m, 1 H), 7.36 (m, 2 H), 7.11 (d, J=7.1 Hz, 2H), 6.94 (d,J=8.3 Hz, 2H), 5.29 (s, 2H); MS: (M⁺H m/z=379.2).

EXAMPLE 372-[4-(1-Methyl-5-pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[4-(5-Pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline butsubstituting methyl hydrazine provided the title compound and2-[4-(1-Methyl-3-pyridin-4-yl-1H-pyrazol4-yl)-phenoxymethyl]-quinoline.¹H NMR (400 MHz, CDCl₃) δ 8.66 (bs, 2 H), 8.17 (d, J=8.7 Hz, 1H), 8.05(d, J=7.9 Hz, 1 H), 7.81 (d, J=8.3 Hz, 1H), 7.70 (m, 1 H), 7.63 (m, 2H), 7.53 (t, J=7.1 Hz, 1 H), 7.21 (m, 2 H), 7.03 (d, J=9.1 Hz, 2H), 6.89(d, J=8.7 Hz, 2H), 5.32 (s, 2H), 3.80 (s, 3H); MS: (M⁺H m/z=393.2).

EXAMPLE 382-[4-(1-Methyl-3-pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[4-(5-Pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline butsubstituting methyl hydrazine provided the title compound and2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline.¹H NMR (400 MHz, CDCl₃) δ 8.49 (bs, 2 H), 8.20 (d, J=8.3 Hz, 1 H), 8.07(d, J=8.3 Hz, 1 H), 7.83 (d, J=8.3 Hz, 1H), 7.74 (m, 2 H), 7.55 (t,J=7.1 Hz, 1 H), 7.42 (m, 2H), 7.38 (s, 1H), 7.17 (d, J=8.7 Hz, 2H) 7.00(d, J=8.7Hz, 2H), 5.38 (s, 2H), 3.95 (s, 3H); MS: (M⁺H m/z=393.2).

EXAMPLE 392-Methyl-1-{4-pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting 1-Hydrazino-2-methyl-propan-2-ol provided the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J=6.2 Hz, 2 H), 8.19 (d,J=8.7 Hz, 1 H), 8.07 (d, J=8.7 Hz, 1 H), 7.82 (d, J=7.9 Hz, 1H), 7.74(t, J=8.3 Hz, 1H), 7.68 (d, J=8.7 Hz, 1 H), 7.62 (s,1H), 7.55 (t, J=7.1Hz, 1 H), 7.39 (d, J=8.7 Hz, 2H), 7.17 (m, 2H), 7.01 (d, J=8.7 Hz, 2H),5.39 (s, 2H) 4.09 (s, 2H), 1.23 (s, 2H); MS: (M⁺H m/z=451.2).

EXAMPLE 402-Methyl-1-{4-pyridin-4-yl-5-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting 1-Hydrazino-2-methyl-propan-2-ol provided the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 8.37 (d, J=5.8 Hz, 2 H), 8.24 (d,J=8.3 Hz, 1 H), 8.09 (d, J=9.1 Hz, 1 H), 7.87 (s, 1H), 7.85 (d, J=7.9Hz, 1H), 7.76 (m, 1 H), 7.72 (m, 1H), 7.17 (m, 4 H), 7.00 (d, J=6.2 Hz,2H), 5.42 (s, 2H) 3.89 (s, 2H), 1.04 (s, 6H); MS: (M⁺H m/z=451.2).

EXAMPLE 41(R)-1-{4-Pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting (R)-1-Hydrazino-propan-2-ol provided the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 8.42 (m, 2 H), 8.18 (d, J=8.3 Hz, 1H), 8.06 (d, J=8.4 Hz, 1 H), 7.81 (d, J=8.3 Hz, 1H), 7.73 (m, 1H), 7.66(d, J=8.7 Hz, 1H), 7.61 (s, 1 H), 7.54 (m, 1H), 7.36 (d, J=9.1 Hz, 2 H),7.12 (m, 2H), 6.99 (d, J=8.7 Hz, 2H) 5.37 (s, 2H), 4.30 (m, 1H), 4.21(dd, J=13.6, 2.5 Hz, 1H), 4.03 (dd, J=13.6, 7.9 Hz, 1H), 1.26 (d, J=6.2Hz, 3H); MS: (M⁺H m/z=437.2).

EXAMPLE 42(S)-1-{4-Pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol

Following the procedure for the preparation of2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting (S)-1-Hydrazino-propan-2-ol provided the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 8.42 (m, 2 H), 8.18 (d, J=8.3 Hz, 1H), 8.06 (d, J=8.4 Hz, 1 H), 7.81 (d, J=8.3 Hz, 1H), 7.73 (m, 1H), 7.66(d, J=8.7 Hz, 1H), 7.61 (s, 1 H), 7.54 (m, 1H), 7.36 (d, J=9.1 Hz, 2 H),7.12 (m, 2H), 6.99 (d, J=8.7 Hz, 2H) 5.37 (s, 2H), 4.30 (m, 1H), 4.21(dd, J=13.6, 2.5 Hz, 1H), 4.03 (dd, J=13.6, 7.9 Hz, 1H), 1.26 (d, J=6.2Hz, 3H), MS: (M⁺H m/z=437.2).

EXAMPLE 432-[4-(1-Isopropyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline

To a solution of2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline (0.075 g)in dimethyl formamide (2 ml) was added cesium carbonate (0.098 g) and2-iodo propane (0.030 ml) and the reaction mixture heated at 60° C. for72 h. The reaction mixture was poured into water and extracted withmethylene chloride, dried magnesium sulfate, filtered and concentrated.Purification via Prep TLC eluting with 2% methanol/1% saturated ammoniumhydroxide/67% ethyl acetate/30% hexane provided the title compound (60mg). ¹H NMR (400 MHz, CDCl₃) δ 8.43 (d, J=6.2 Hz, 2 H), 8.16 (d, J=8.7Hz, 1 H), 8.05 (d, J=9.1 Hz, 1 H), 7.80 (d, J=8.3 Hz, 1H), 7.70 (m, 1H),7.65 (d, J=8.7 Hz, 1 H), 7.59 (s, 1H), 7.53 (t, J=7.1 Hz, 1 H), 7.38 (d,J=9.1 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 5.38 (s,2H) 4.51 (m, 1H), 1.54 (d, J=6.6 Hz, 6H); MS: (M⁺H m/z=421.2).

EXAMPLE 442-[4-(1-Isobutyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[4-(1-Isopropyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting 1-Iodo-2-methyl-propane provided the title compound. ¹HNMR (400 MHz, CDCl₃) δ 8.44 (m, 2H), 8.18 (d, J=8.7 Hz, 1H), 8.06 (d,J=8.3 Hz, 1 H), 7.83 (d, J=6.6 Hz, 1 H), 7.73 (t, J=6.6 Hz, 1H), 7.54(s,1H), 7.52 (m, 1H), 7.38 (d, J=9.1 Hz, 2 H), 7.15 (m, 2H), 7.00 (d,J=8.7 Hz, 2 H), 5.38 (s, 2H) 3.93 (d, J=7.5 Hz, 2 H), 4.29 (m, 1H), 0.95(d, J=6.6 Hz, 6H); MS: (M⁺H m/z=435.2).

EXAMPLE 452-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-[1.8]Naphthyridine

To a solution of 4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol (72mg) in dioxane 1.5 ml, was added triphenyl phosphine (121 mg),[1,8]Naphthyridin-2-yl-methanol (69 mg) and di-t-butyl-diazacarboxalate(106 mg) and the reaction mixture heated at 60° C. for 24 h. Thereaction mixture was poured into 1 N NaOH, extracted with methylenechloride, dried magnesium sulfate and concentrated. Purification viaPrep TLC eluting with 15% methanol/70%ethyl acetate/15% hexanes providedthe title compound (9.8 mg). ¹H NMR (400 MHz, CDCl₃) δ 9.13 (dd, J=4.2,1.7 Hz, 1H), 8.45 (d, J=5.8 Hz, 2H), 8.23 (d, J=8.3 Hz, 1H), 7.21 (dd,J=8.5, 2.1 Hz, 1 H), 7.79 (d, J=8.7 Hz, 1H), 7.57 (s, 1H), 7.52 (m, 1H),7.37(d, J=9.1 Hz, 2 H), 7.16 (d, J=6.2 Hz, 2H), 7.01 (d, J=8.7 Hz, 2 H),5.47 (s, 2H), 3.94 (s, 3 H); MS: (M⁺H m/z=394.0).

Preparation 30

4-(2-Quinolin-2-yl-ethyl)-benzoic acid methyl ester

To a solution of 4-[Triphenyl-phophanyl)-methyl]-benzoic acid methylester (1.87 g) in THF (16 ml) under N₂ atmosphere at 0° C. was addedsodium hydride (165 mg (60%)). After 30 min, quinoline-2-carbaldehyde(0.50 g) was added and the reaction stirred at ambient temperature for 2h. The reaction mixture was quenched with brine, extracted withchloroform, dried magnesium sulfate, filtered and concentrated toprovide the crude alkene. The crude product was placed on a parr shakerin ethanol (15 ml) with palladium hydroxide (200 mg) as the catalystunder 10 PSI of H₂. After 40 min, the reaction mixture was filteredthrough celite and concentrated. Biotage MPLC chromatography elutingwith 10-20% ethyl acetate/hexane provided the title compound. MS: (M⁺Hm/z=292.1).

Preparation 31

4-(2-Quinolin-2-yl-ethyl)-benzoic acid

To a solution of 4-(2-Quinolin-2-yl-ethyl)-benzoic acid methyl ester(680 mg) in THF (11 ml)/methanol (3 ml) was added 1N sodium hydroxidesolution (4.67 ml). The reaction mixture stirred for 4 h. and the pHadjusted to 3. The white solid was filtered to provide the titlecompound (550 mg, 86%). MS: (M⁺H m/z=278.1).

Preparation 32

N-Methoxy-N-methyl-4-(2-quinolin-2-yl-ethyl)-benzamide

To a solution of 4-(2-Quinolin-2-yl-ethyl)-benzoic acid (530 mg) indioxane 5 ml/acetonitrile 5 ml was added triethylamine (0.60 ml) andO,N-Dimethyl-hydroxylamine hydrogen chloride (240 mg). After 72 h, thereaction mixture was poured into 1N sodium hydroxide solution andextracted with chloroform, dried magnesium sulfate, filtered andconcentrated. Biotage MPLC chromatography eluting with 20-50% ethylacetate provided the title compound (516 mg, 88%). MS: (M⁺H m/z=321.1).

Preparation 33

2-Pyridin-4-yl-1-[4-(2-quinolin-2-yl-ethyl)-phenyl]-ethanone

Following the procedure for the preparation of2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone butsubstituting N-Methoxy-N-methyl-4-(2-quinolin-2-yl-ethyl)-benzamideprovided the title compound. MS: (M⁺H m/z=353.1).

EXAMPLE 462-{2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline

To 2-Pyridin-4-yl-1-[4-(2-quinolin-2-yl-ethyl)-phenyl]-ethanone (53 mg)was added 3 ml of Diethoxymethyl-dimethyl-amine and the reaction mixtureheated at 100° C. After 3 h, the reaction mixture as concentrated andmethanol (3 ml) and hydrazine (0.02 ml) was added. The reaction mixturewas heated at 60° C. for 3 h and concentrated. Biotage MPLC purificationeluting with 1-3% methanol/0.5% saturated ammonium hydroxide inchloroform provided the title compound. ¹H NMR (400 MHz, CDCl₃) δ 8.47(d, J=6.2 Hz, 2 H), 8.05 (d, J=8.3 Hz, 2 H), 7.80 (s, 1H), 7.78 (d,J=8.3 Hz, 2 H), 7.70 (t, J=7.1 Hz, 1H), 7.51 (t, J=7.1 Hz, 1 H), 7.32(d, J=8.3 Hz, 2 H), 7.24 (m, 3H), 7.19 (d, J=6.2 Hz, 2H), 3.31 (m, 2H),3.22 (m, 2H), MS: (M⁺H m/z=377.1).

EXAMPLE 472-(2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-ethyl]-quinoline

Following the procedure for the preparation of2-{2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline butsubstituting methyl hydrazine provided the title compound. ¹H NMR (400MHz, CDCl₃) δ 8.45 (d, J=6.2 Hz, 2 H), 8.06 (t, J=10.4 Hz, 2 H), 7.77(d, J=7.1 Hz, 1 H), 7.70 (t, J=8.3 Hz, 1 H), 7.57 (s, 1H), 7.50 (t,J=9.1 Hz, 1 H), 7.35 (d, J=8.3 Hz, 2H), 7.24 (m, 3H), 7.20 (d, J=5.0 Hz,2H), 3.97 (s, 3H), 3.31 (m, 2H), 3.18 (m, 2H); MS: (M^(+H m/z=)391.0).

Preparation 34

2-(2-Chloro-pyridin-4-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone

Following the procedure for the preparation of2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone butsubstituting 2-chloro-4-methyl pyridine provided the title compound. MS:(M⁺H m/z=389.0).

EXAMPLE 482-{4-[4-(2-Chloro-pyridin-4-yl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline

Following the procedure for the preparation of2-{2-[4-(4-Pyridin4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline butsubstituting2-(2-Chloro-pyridin-4-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanoneprovided the title compound. ¹H NMR (400 MHz, CDCl₃) δ 8.23 (m, 2 H),8.08 (d, J=8.7 Hz, 1 H), 7.83 (d, J=8.3 Hz, 1 H), 7.80 (s, 1H), 7.75 (t,J=7.1 Hz, 1 H), 7.67 (d, J=8.3 Hz, 1H), 7.57 (t, J=7.1 Hz, 1 H), 7.33(d, J=9.1 Hz, 2H), 7.05 (m, 4H), 5.40 (s, 2H); MS: (M⁺H m/z=413.1).

EXAMPLE 492-{4-[4-(2-Chloro-pyridin-4-yl)-1-methyl-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline

Following the procedure for the preparation of2-2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline butsubstituting methyl hydrazine and2-(2-Chloro-pyridin-4-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanoneprovided the title compound. ¹H NMR (400 MHz, CDCl₃) δ 8.19 (m, 2 H),8.07 (d, J=8.3 Hz, 1 H), 7.83 (d, J=8.3 Hz, 1 H), 7.74 (t, J=8.3 Hz,1H), 7.67 (d, J=8.3 Hz, 1 H), 7.58 (s, 1H), 7.55 (t, J=8.3 Hz, 1 H),7.36 (d, J=8.7 Hz, 2H), 7.20 (s, 1H), 7.03 (m, 3H), 5.40 (s, 2H) 3.95(s, 3H); MS: (M⁺H m/z=427.0).

EXAMPLE 502-{4-[1-Methyl-4-(2-methyl-pyridin-4-yl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline

To a solution of2-{4-[4-(2-Chloro-pyridin-4-yl)-1-methyl-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline(100 mg) in dioxane (1.2 ml) was added methyl boroxine (0.066 ml),palladium tetrakis (41 mg) and 2N sodium carbonate solution (0.234 ml).The reaction mixture was heated at 100° C. for 8 h, poured into 1 NNaOH, extracted with chloroform, dried magnesium sulfate, filtered andconcentrated. Prep TLC run with 3% methanol/0.5% saturated ammoniumhydroxide/80% ethyl acetate in hexanes provided the free base material.The produce was stirred in ethyl acetate and 2 eq. of succinic acid wasadded to give a white precipitate which was filtered to provide thetitle compound as a white solid succinate salt (20 mg). ¹H NMR (400 MHz,DMSO) δ 8.40 (d, J=8.3 Hz, 2 H), 8.25 (d, J=5.0 Hz, 2 H), 8.07 (s, 1H),8.00 (t, J=7.9 Hz, 2 H), 7.77 (t, J=6.6 Hz, 1 H), 7.67 (d, J=8.7 Hz,2H), 7.60 (t, J=6.6 Hz, 1 H), 7.29 (d, J=9.1 Hz, 2H), 7.03 (m, 3 H),6.92 (m, 1H), 5.35 (s, 2H), 3.85 (s, 3H), 2.37 (s, 4H) 2.31 (s, 3H); MS:(M⁺H m/z=407.0).

EXAMPLE 51Dimethyl-(4-{1-methyl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-1H-pyrazol-4-yl}-pyridin-2-yl)-amine

To a solution of2-{4-[4-(2-Chloro-pyridin-4-yl)-1-methyl-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline(100 mg) in dimethyl formamide (1 ml) was added diethanolamine (0.035ml) and the reaction mixture heated at 130° C. for 72 h. The reactionmixture was poured into water and extracted with ethyl ether, driedmagnesium sulfate, filtered and concentrated. Prep TLC eluting with 60%ethyl acetate/hexane provided the title compound as a Free base. Theproduct was stirred in ethyl acetate and 1 eq. of succinic acid wasadded. After 18 h, the white precipitate was filtered to provide thesuccinate salt (24 mg). ¹H NMR (400 MHz, DMSO) δ 8.40 (d, J=8.3 Hz, 1H), 8.03 (s, 1 H), 7.98 (m, 2 H), 7.90 (d, J=5.4 Hz, 1 H), 7.77 (m, 1H),7.65 (d, J=8.3 Hz, 1 H), 7.59 (m, 1 H), 7.31 (d, J=6.6 Hz, 2H), 7.04 (d,J=9.1 Hz, 2 H), 6.37 (m, 2 H), 5.35 (s, 2H), 3.84 (s, 3H), 2.80 (s, 6H)2.37 (s, 4H); MS: M⁺H m/z=436.0).

Preparation 35

3-Dimethylamino-1-pyridin-4-yl-propenone

To 1-Pyridin-4-yl-ethanone(1.62 g) was added N,N-dimethylformamidediethylacetal (10 ml) and the reaction mixture heated at 120° C. for 2 hand concentrated to provide the title compound. MS: (M⁺H m/z=177.0).

Preparation 36

4-[2-(4-Benzyloxy-phenyl-2H-pyrazol-3-yl]-pyridine

To a solution of 3-Dimethylamino-1-pyridin-4-yl-propenone (590 mg) inmethanol (10 ml) was added acetic acid (0.5 ml) and(4-Benzyloxy-phenyl)-hydrazine hydrogen chloride (836 mg) and thereaction mixture heated to 60° C. for 6 h. The reaction mixture waspoured into saturated sodium bicarbonate, extracted with ethyl acetate,dried magnesium sulfate, filtered and concentrated. Purification viacombiflash MPLC provided the title compound (795 mg). MS: (M⁺Hm/z=328.1).

Preparation 37

4-(5-Pyridin-4-yl-pyrazol-1-yl)-phenol

To a solution of 4-[2-(4-Benzyloxy-phenyl-2H-pyrazol-3-yl]-pyridine (610mg) in ethyl acetate (15 ml)/ethanol (15 ml) was added palladiumhydroxide (20%, 343 mg). The reaction mixture was placed on a parrshaker under 45 psi of H₂ gas for 18 h. The reaction mixture wasfiltered through celite and concentrated. Purification via chromatotron(2 mm silica, 5% methanol/chloroform) provided the title compound (259mg). MS: (M⁺H m/z=238.1).

EXAMPLE 52 2-[4-(5-Pyridin-4-yl-pyrazol-1-yl)-phenoxymethyl]-quinoline

To a solution of 4-(5-Pyridin-4-yl-pyrazol-1-yl)-phenol (82 mg) inacetone was added potassium carbonate (153 mg) and2-Chloromethyl-quinoline (95 mg) and the reaction mixture heated at 60°C. for 18 h. The reaction mixture was poured into brine and extractedwith ethyl acetate, dried magnesium sulfate, filtered and concentrated.Purification via combiflash MPLC provided the title compound (91 mg). ¹HNMR (400 MHz, CDCl₃) δ 8.51 (m, 2 H), 8.20 (d, J=8.7 Hz, 1 H), 8.06 (d,J=8.7 Hz, 1 H), 7.83 (d, J=7.1 Hz, 1H), 7.74 (m, 2H), 7.65 (d, J=8.7 Hz,1 H), 7.57 (m, 1H), 7.20 (d, J=8.7 Hz, 2 H), 7.09 (d, J=5.8 Hz, 2H),7.02 (d, J=9.1 Hz, 2H), 6.60 (d, J=1.7 Hz, 1H), 5.39 (s, 2H); MS: (M⁺Hm/z=379.0).

EXAMPLE 532-[4-(3-Methyl-5-pyridin-4-yl-pyrazol-1-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[4-(5-Pyridin-4-yl-pyrazol-1-yl)-phenoxymethyl]-quinoline butsubstituting (1,1-Dimethoxy-ethyl)-dimethyl-amine provided the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=6.2 Hz, 2 H), 8.20 (d,J=8.3 Hz, 1 H), 8.06 (d, J=8.7 Hz, 1 H), 7.83 (d, J=8.3 Hz,1H), 7.74(m,1H), 7.64 (d, J=8.3 Hz, 1 H), 7.54 (m, 1H), 7.18 (d, J=8.7 Hz, 2 H),7.07 (d, J=6.2 Hz, 2H), 7.00 (d, J=9.1 Hz, 2H), 6.40 (s, 1H), 5.38 (s,2H), 2,35 (s, 3H); MS: (M⁺H m/z=393.4).

Preparation 38

3-Chloro-4-(quinolin-2-ylmethoxy)-benzoic acid methyl ester

Following the procedure for the preparation of4-(Quinolin-2-ylmethoxy)-benzoic acid methyl ester but substituting3-Chloro-4-hydroxy-benzoic acid methyl ester provided the titlecompound. MS: (M⁺H m/z=328.0).

Preparation 39

3-Chloro-4-(quinolin-2-ylmethoxy)-benzoic acid

Following the procedure for the preparation of4-(Quinolin-2-ylmethoxy)-benzoic acid but substituting3-Chloro-4-(quinolin-2-ylmethoxy)-benzoic acid methyl ester provided thetitle compound. (M⁺H m/z=314.0).

Preparation 40

3-Chloro-N-methoxy-N-methyl4-(quinolin-2-ylmethoxy)-benzamide

Following the procedure for the preparation ofN-Methoxy-N-methyl-4-(2-quinolin-2-yl-ethyl)-benzamide but substituting3-Chloro4-(quinolin-2-ylmethoxy)-benzoic acid provided the titlecompound. (M⁺H m/z=356.9).

Preparation 41

1-[3-Chloro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanone

Following the procedure for the preparation of2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone butsubstituting3-Chloro-N-methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide providedthe title compound. (M⁺H m/z=389.0).

EXAMPLE 542-[2-Chloro4-(4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-{2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline butsubstituting1-[3-Chloro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanoneprovided the title compound. ¹H NMR (400 MHz, CD₃OD) δ 8.37 (m, 4 H),8.02 (d, J=8.7 Hz, 2 H), 7.93 (d, J=8.3 Hz, 2H), 7.78 (m, 2 H), 7.61 (t,J=7.1 Hz, 1 H), 7.31 (m, 2H), 7.21 (m, 1 H), 5.44 (s, 2H); MS: (M⁺Hm/z=413.0).

EXAMPLE 552-[2-Chloro-4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-{2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline butsubstituting methyl hydrazine and1-[3-Chloro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanoneprovided the title compound. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J=6.2Hz, 2 H), 8.21 (d, J=8.3 Hz, 1 H), 8.04 (d, J=7.5 Hz, 1H), 7.83 (d,J=8.3 Hz, 1 H), 7.78 (d, J=8.7 Hz, 1 H), 7.72 (m, 1H), 7.56 (m, 3 H),7.21 (m, 1H), 7.14 (d, J=6.2 Hz, 2 H), 6.97 (d, J=8.7 Hz, 1 H), 5.46 (s,2H), 3.95 (s, 3H); MS: (M⁺H m/z=427.1).

Preparation 42

4-(4-Pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-phenol

To a solution of 4-Methoxy-N-pyridin-4-yl-benzamide (75 mg) in POCl₃ (3ml) was added PCl₅ (68 mg) and the reaction mixture heated at reflux for5 h. The reaction mixture was concentrated and dissolved in dimethylformamide (2 ml) and Formic acid hydrazide (5 eq, 100 mg) was added andstirred for 2 h. The reaction mixture was concentrated and diluted withisopropanol (3 mL) and 0.25 ml of conc. HCl was added. The reactionmixture stirred for 18 h, quenched with 1 NaOH, extracted withdichloromethane, dried magenesium sulfate and concentrated. The crudeproduct dissolved in methylene chloride (2 mL) and boron tribromide(0.63 mL 1.0M hexanes) was added at 0° C. The reaction mixture waswarmed to ambient temperature and stirred for 18 h. The reaction mixturewas quenched with 1 N NaOH and pH adjusted to 9, extracted withdichloromethane, dried magnesium sulfate, filtered and concentrated.Purification via Biotage MPLC chromatography eluting with 0-20%methanol/methylene chlroride provided the title compound (32 mg, 55%).MS: (M⁺H m/z=239.2).

EXAMPLE 562-[4-(4-Pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-phenoxymethyl]-quinoline

To a solution of 4-(4-Pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-phenol (44mg) in dimethyl formamide (1 ml) in a 7 ml Teflon capped vial was addedcesium carbonate (185 mg) and 2-Chloromethyl-quinoline (37 mg) and thereaction mixture heated on a shaker plate at 60° C. for 18 h. Thereaction mixture was poured into water and extracted with methylenechloride, dried magnesium sulfate, filtered and concentrated to providethe title compound (45 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.87 (s, 1H), 8.65(d, J=6.0 Hz, 2 H), 8.37 (d, J=8.3 Hz, 1 H), 8.03 (d, J=8.7 Hz, 1H),7.94 (d, J=7.9 Hz, 1H), 7.78 (m, 1 H), 7.70 (d, J=8.3 Hz, 1 H), 7.61 (t,J=5.8 Hz, 1 H), 7.40 (m, 4H), 7.14 (d, J=9.1 Hz, 2 H), 5.38 (s, 2H); MS:(M⁺H m/z=380.2).

Preparation 43

[4-(Quinolin-2-ylmethoxy)-phenyl]-hydrazine

To a suspension of 4-(Quinolin-2-ylmethoxy)-phenylamine (1.73 g) in 30mL of concentrated HCl at 0° C. was added sodium nitrite (531 mg). After3 h, tin chlrodie (3.95 g) was dissolved in 20 mL of concentrated HCland added slowly dropwise and the reaction mixture stirred at ambienttemperature for 18 h. The reaction mixture was filtered and the soliddried to provide the title compound as the HCL salt (3.94 g). MS: (M⁺Hm/z=266.3).

EXAMPLE 572-[4-(5-Pyridin4-yl-[1,2,4]triazol-1-yl)-phenoxymethyl]-quinoline

Isonicatinamide (4.15 g) was heated in 35 ml of N,N-Dimethylformamidediethyl acetal at reflux for 3 h. The reaction mixture was cooled toambient temperature and concentrated to give 5.02 g ofN-Dimethylaminomethylene-isonicotinamide. To a solution of[4-(Quinolin-2-ylmethoxy)-phenyl]-hydrazine (3.16 g) in methanol (30 mL)and acetic acid (2.5 mL) was addedN-Dimethylaminomethylene-isonicotinamide (1.10 g) and the reactionmixture heated at reflux for 72 h. The reaction mixture was concentratedonto silica gel and purified by flash chromatography to provided thetitle compound (514 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.60 (d, J=5.8 Hz, 2H), 8.22 (d, J=8.7 Hz, 1 H), 8.10 (s, 1H), 8.07 (d, J=8.7 Hz, 1H), 7.85(d, J=7.1 Hz, 1H), 7.76 (m, 1 H), 7.66 (d, J=8.3 Hz, 1 H), 7.56 (m, 1H), 7.56 (m, 1H), 7.38 (d, J=6.2 Hz, 2 H), 7.26 (d, J=8.7Hz, 2H), 7.11(d, J=9.1 Hz, 2H), 5.42 (s, 2H); MS: (M⁺H m/z=380.3).

Preparation 44

[4-(Quinolin-2-ylmethoxy)-phenyl]-hydrazine

Following the procedure for the preparation of(4-(Quinolin-2-ylmethoxy)-phenyl]-hydrazine but substituting4-(Quinolin-2-ylmethoxy)-phenylamine provided the title compound. MS:(M⁺H m/z=266.2).

EXAMPLE 582-[4-(3-Methyl-5-pyridin-4-yl-[1,2,4]triazol-1-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[4-(5-Pyridin-4-yl-[1,2,4]triazol-1-yl)-phenoxymethyl]-quinoline butsubstituting N,N-dimethylacetamide dimethyl acetal provided the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d, J=6.2 Hz, 2 H), 8.22 (d,J=8.3 Hz, 1 H), 8.08 (d, J=8.3 Hz, 1H), 7.84 (d, J=7.7 Hz, 1H), 7.74 (m,1 H), 7.65 (d, J=8.3 Hz, 1 H), 7.56 (m, 1 H), 7.36 (d, J=6.2 Hz, 2 H),7.25 (d, J=9.1 Hz, 2H), 7.09 (d, J=8.7 Hz, 2H), 5.41 (s, 2H), 2.48 (s,3H); MS: (M⁺H m/z=394.4).

Preparation 45

4-(Quinolin-2-ylmethoxy)-benzamide

To a solution of 2-Chloromethyl-quinoline (1.57 g) and4-Hydroxy-benzamide (995 mg) in dimethyl formamide (20 mL) was addedcesium carbonate (7.3 g) and the reaction mixture heated at 80° C. for18 h. The reaction mixture was poured into water and extracted withchloroform, dried magnesium sulfate, filtered and concentrated toprovided the title compound (909 mg). MS: (M⁺H -m/z=279.3).

EXAMPLE 592-[4-(2-Pyridin-4-yl-2H-[1,2,4]triazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[4-(5-Pyridin-4-yl-[1,2,4]triazol-1-yl)-phenoxymethyl]-quinoline butsubstituting 4-(Quinolin-2-ylmethoxy)-benzamide andPyridin-4-yl-hydrazine provided the title compound. ¹H NMR (400 MHz,CDCl₃) δ 8.65 (d, J=6.2 Hz, 2 H), 8.21 (d, J=8.3 Hz, 1 H), 8.08 (s, 1H),8.07 (d, J=7.9 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.73 (m, 1 H), 7.65 (d,J=8.7 Hz, 1 H), 7.55 (m, 1 H), 7.43 (d, J=9.1 Hz, 2H), 7.32 (d, J=6.2Hz, 2 H), 7.05 (d, J=8.7Hz, 2H), 5.40 (s, 2H); MS: (M⁺H m/z=380.2).

EXAMPLE 602-[4-(5-Methyl-2-pyridin-4-yl-2H-[1,2,4]triazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-[4-(5-Pyridin-4-yl-[1,2,4]triazol-1-yl)-phenoxymethyl]-quinoline butsubstituting 4-(Quinolin-2-ylmethoxy)-benzamide, Pyridin4-yl-hydrazineand N,N-dimethylacetamide dimethyl acetal provided the title compound.¹H NMR (400 MHz, CDCl₃) δ 8.61 (d, J=6.2 Hz, 2 H), 8.21 (d, J=8.7 Hz, 1H), 8.07 (d, J=7.9 Hz, 1H, 7.83 (d, J=8.3 Hz, 1H), 7.75 (m, 1 H), 7.64(d, J=8.3 Hz, 1 H), 7.55 (m, 1 H), 7.56 (m, 1H), 7.41 (d, J=9.1 Hz, 2H), 7.29 (d, J=6.2 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 5.40 (s, 2H), 2.47(s, 3H); MS: (M⁺H m/z=394.3).

Preparation 46

4-[3-(4-Benzyloxy-phenyl)-1H-pyrazol-4-yl]-pyridine

To a solution of 1-(4-Benzyloxy-phenyl)-2-pyridin-4-yl-ethanone (1.58 g)was added toluene (26 ml) and 1.6 g of Diethoxymethyl-dimethyl-amine andthe reaction mixture heated at reflux for 1 h. The reaction mixture wasconcentrated, dissolved in methanol (26 ml) and hydrazine (0.64 g) andthe reaction mixture was heated at reflux for 1 h. The reaction mixturewas concentrated and purified via biotage MPLC eluting with 5%methanol/chloroform/0.5% ammonium hydroxide to provided the titlecompound (0.89 g). MS: (M⁺H m/z=328.1).

Preparation 47

4-[3-(4-Benzyloxy-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol4-yl]-pyridine

To a solution of 4-[3-(4-Benzyloxy-phenyl)-1H-pyrazol-4-yl]-pyridine(0.42 g) in dimethyl formamide (7 ml) was added cesium carbonate (0.65g) and 1,1,1-Trifluoro-2-iodo-ethane (0.29 ml). The reaction mixture washeated at 60° C. for 24 h, poured into water and extracted 3× withdichloromethane. Purification via biotage MPLC chromatography, elutingwith 5% methanol/0.5% ammonium hydroxide/70% ethyl acetate/hexaneprovided the title compound. MS: (M⁺H m/z=410.0).

Preparation 48

4-[4-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenol

Following the procedure for the preparation of4-(1-Methyl4-pyridin4-yl-1H-pyrazol-3-yl)-phenol but substituting4-[3-(4-Benzyloxy-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-4-yl]-pyridineprovided the title compound. MS: (M⁺H m/z=320.1)

EXAMPLE 612-{4-[4-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoxaline

To a solution of4-[4-Pyridin4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenol (79mg) and Quinoxalin-2-yl-methanol (50 mg) in dioxane (2 ml) was addedtriphenylphosphine (105 mg) and di-t-butyldiazacarboxalate (92 mg) andthe reaction mixture heated at 60° C. After 18, the reaction mixture waspoured into 1N NaOH, extracted with methylene chloride, dried magnesiumsulfate, filtered and concentrated. Purification with MPLC biotageeluting with 2% methanol/0.5% ammonium hydroxide/60% ethylacetate/hexanes provided the title compound (54 mg). ¹H NMR (400 MHz,CDCl₃) δ 9.09 (s, 1 H), 8.52 (m, 2H), 8.13 (m, 1H), 8.10 (m, 1H), 7.79(m, 2 H), 7.73 (s, 1 H), 7.40 (d, J=8.7, Hz, 2 H), 7.24 (m, 2H), 7.04(d, J=8.7 Hz, 2 H), 5.32 (s, 2H), 4.79 (q, J=8.3 Hz, 2 H); MS: (M⁺Hm/z=462.1).

EXAMPLE 628-Methoxy-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-{4-[4-Pyridin4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoxalinebut substituting 4-(1-Methyl4-pyridin4-yl-1H-pyrazol-3-yl)-phenol and(8-Methoxy-quinolin-2-yl)-methanol provided the title compound. ¹H NMR(400 MHz, CDCl₃) δ 8.45 (d, J=6.2 Hz, 2 H), 8.15 (d, J=8.7 Hz, 1H), 7.73(d, J=8.3 Hz,1H), 7.55 (s, 1H), 7.44 (m, 1 H), 7.37 (m, 3 H), 7.15 (d,J=5.8, Hz, 2 H), 7.07 (d, J=7.5 Hz, 1H), 6.99 (d, J=8.7 Hz, 2 H), 5.46(s, 2H), 4.08 (s, 3 H), 3.94 (s, 3H); MS: (M⁺H m/z=423.1).

EXAMPLE 632-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-pyrido[1,2-a]pyrimidin-4-one

Following the procedure for the preparation of2-[4-(4-Pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-phenoxymethyl]-quinolinebut substituting 2-Chloromethyl-pyrido[1,2-a]pyrimidin4-one provided thetitle compound. ¹H NMR (400 MHz, CDCl₃) δ 9.01 (d, J=7.1 Hz, 1 H), 8.43(m, 2H), 7.72 (m, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.53 (s, 1H), 7.37 (d,J=9.1 Hz, 2H), 7.12 (m, 3H), 6.93 (d, J=8.7Hz, 2H), 6.68 (s, 1 H), 5.05(s, 2H), 3.92 (s, 3H); MS: (M⁺H m/z=410.1).

EXAMPLE 642-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinazoline

Following the procedure for the preparation of2-[4-(4-Pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-phenoxymethyl]-quinolinebut substituting 2-Chloromethyl-quinazoline provided the title compound.¹H NMR (400 MHz, CDCl₃) δ 9.43 (s, 1H), 4.43 (d, J=4.6 Hz, 2 H), 8.07(d, J=8.3 Hz, 1H), 7.93 (d, 2H), 7.69 (t, J=7.9 Hz, 1H), 7.55 (s, 1 H),7.36 (d, J=8.7 Hz, 2 H), 7.15 (d, J=6.2, Hz, 2 H), 7.05 (d, J=8.7 Hz,2H), 5.48 (s, 2H), 3.94 (s, 3H); MS: (M⁺H m/z=394.2)

Preparation 49

4-Benzyloxy-2-fluoro-benzoic acid benzyl ester

Following the procedure for the preparation of4-(Quinolin-2-ylmethoxy)-benzoic acid methyl ester but substituting twoequivalents of benzyl bromide and 2-Fluoro4-hydroxy-benzoic acidprovided the title compound. MS: (M⁺H m/z=337.2).

Preparation 50

4-Benzyloxy-2-fluoro-benzoic acid

Following the procedure for the preparation of4-(Quinolin-2-ylmethoxy)-benzoic acid but substituting4-Benzyloxy-2-fluoro-benzoic acid benzyl ester provided the titlecompound. MS: (M⁺H m/z=247.1).

Preparation 51

4-Benzyloxy-2-fluoro-N-methoxy-N-methyl-benzamide

Following the procedure for the preparation ofN-Methoxy-N-methyl4-(quinolin-2-ylmethoxy)-benzamide but substituting4-Benzyloxy-2-fluoro-benzoic acid provided the title compound. MS: (M⁺Hm/z=290.2).

Preparation 52

1-(4-Benzyloxy-2-fluoro-phenyl)-2-pyridin-4-yl-ethanone

Following the procedure for the preparation of2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone butsubstituting 4-Benzyloxy-2-fluoro-N-methoxy-N-methyl-benzamide providedthe title compound. MS: (M⁺H m/z=322.1).

Preparation 53

4-[3-(4-Benzyloxy-2-fluoro-phenyl)-l -methyl-1H-pyrazol-4-yl]-pyridine

Following the procedure for the preparation of4-[3-(4-Benzyloxy-phenyl)-1-methyl-1H-pyrazol4-yl]-pyridine butsubstituting 1-(4-Benzyloxy-2-fluoro-phenyl)-2-pyridin4-yl-ethanoneprovided the title compound. MS: (M⁺H m/z=360.1).

Preparation 54

3-Fluoro-4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol

Following the procedure for the preparation of4-(1-Methyl4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol but substituting4-[3-(4-Benzyloxy-2-fluoro-phenyl)-1-methyl-i H-pyrazol4-yl]-pyridineprovided the title compound. MS: (M⁺H m/z=270.1).

EXAMPLE 652-[3-Fluoro-4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline

To a solution of3-Fluoro-4-(1-methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenol (450 mg) indimethylformamide (10 ml) was added cesium carbonate (2 g) and 2-chloromethyl quinoline (481 mg) and the reaction mixture was heated at 60° C.for 18 h. The reaction mixture was poured into 1N NaOH, extracted withmethylene chloride, dried magnesium sulfate, filtered and concentrated.Biotage MPLC purification eluting with methanol 2%/0.5% ammoniumhydroxide/70% ethyl acetate/hexanes provided the title compound. Thefree base was stirred in ethyl acetate and 1.1 equivalents of succinicacid was added. The white precipitate was filtered and dried to providethe title compound as the succinate salt (280 mg). ¹H NMR (400 MHz,DMSO) δ 8.43 (d, J=8.3 Hz, 1 H), 8.37 (d, J=6.2 Hz, 2H), 8.26 (s, 1H),8.00 (m, 2H), 7.78 (t, J=7.1 Hz, 1H), 7.70 (d, J=8.3 Hz, 1 H), 7.61 (t,J=6.6 Hz, 1 H), 7.38 (t, J=8.3, Hz, 1 H), 7.10 (d, J=6.2 Hz, 2H), 7.00(m, 2H), 5.40 (s, 2H), 3.88 (s, 3 H), 2.38 (s, 4H), MS: (M⁺H m/z=411.1).

Preparation 55

4-[3-(4-Benzyloxy-2-fluoro-phenyl)-1H-pyrazol-4-yl]-pyridine

Following the procedure for the preparation of2-[4-(4-Pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline butsubstituting 1-(4-Benzyloxy-2-fluoro-phenyl)-2-pyridin-4-yl-ethanoneprovided the title compound. MS: (M⁺H m/z=346.3).

Preparation 56

4-[3-(4-Benzyloxy-2-fluoro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-4-yl]-pyridine

Following the procedure for the preparation of2-{4-[-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinolinebut substituting4-[3-(4-Benzyloxy-2-fluoro-phenyl)-1H-pyrazol4-yl]-pyridine provided thetitle compound. MS: (M⁺H m/z=428.4).

Preparation 57

3-Fluoro-4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenol

To4-[3-(4-Benzyloxy-2-fluoro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-4-yl]-pyridine(900 mg) was added trifluoroacetic acid (5.25 ml) and anisole (1.15 ml)and the reaction mixture heated at reflux for 18 h. The reaction mixturewas quenched with with 1N NaOH, extracted 3× tetrahydrofuran, driedmagnesium sulfate, filtered and concentrated. Purification via BiotageMPLC eluting with 5% methanol/1% ammonium hydroxide/ethyl acetateprovided the title compound (552 mg). MS: (M⁺H m/z=338.2).

EXAMPLE 662-{3-Fluoro-4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline

Following the procedure for the preparation of2-[3-Fluoro4-(1-methyl4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting3-Fluoro4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoland acetone as the solvent provided the title compound. ¹H NMR (400 MHz,CDCl₃) δ 8.46 (m, 2 H), 7.80 (s, 1H), 7.31 (t, J=8.3 Hz, 1H), 7.24 (m, 5H), 6.72 (dd, J=8.3, 2.5 Hz, 1 H), 6.50 (dd, J=11.6, 2.1 Hz, 1 H), 4.81(q, J=8.4 Hz, 2H); MS: (M⁺H m/z=479.2).

EXAMPLE 672-{3-Fluoro-4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoxaline

Following the procedure for the preparation of2-[3-Fluoro4-(1-methyl4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinebut substituting3-Fluoro4-[4-pyridin4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenol,2-Chloromethyl-quinoxaline and acetone as the solvent provided the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 9.09 (s, 1 H), 8.46 (m, 2H), 8.15(m, 1H), 8.09 (m, 1 H), 7.81 (m, 3H), 7.43 (t, J=8.7Hz, 1H), 7.12 (d,J=6.2 Hz, 2H), 6.93 (dd, J=7.9, 2.0 Hz, 1 H), 6.81 (dd, J=11.6, 2.5 Hz,1 H), 5.43 (s, 2H), 4.80 (q, J=8.3 Hz, 2H); MS: (M⁺H m/z=480.1).

EXAMPLE 684-Chloro-2-[4-(1-methyl4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline

Following the procedure for the preparation of2-{4-[4-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoxalinebut substituting 4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenol and(4-Chloro-quinolin-2-yl)-methanol provided the title compound. ¹H NMR(400 MHz, CDCl₃) δ 8.43 (d, J=4.6 Hz, 2 H), 8.18 (d, J=8.7 Hz, 1H), 8.04(d, J=7.9 Hz, 1H), 7.73 (m, 2H), 7.60 (t, J=7.1 Hz, 1 H), 7.52 (s, 1 H),7.37 (d, J=9.1, Hz, 2 H), 7.12 (d, J=6.2 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 5.30 (s, 2H), 3.90 (s, 3 H); MS: (M⁺H m/z=427.1).

EXAMPLE 694-Methoxy-2-[4-(1-methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline

To a solution of4-Chloro-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline(125 mg) in methanol (4 mL) was added phenanthroline (78 mg), cesiumcarbonate (143 mg) and copper iodide (5 mg). The reaction mixture washeated in a microwave reactor at 165° C. with 50 W of power for 20 min.The reaction mixture was filtered through celite and concentrated.Purification via MPLC biotage chromatography, eluting with 5%methanol/1% ammonium hydroxide/methylene chloride provided the titlecompound (74 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=5.4 Hz, 2 H),8.18 (d, J=8.3 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.68 (m, 1H), 7.55 (s,1H), 7.49 (t, J=7.1 Hz, 1 H), 7.37 (d, J=9.1, Hz, 2 H), 7.15 (d, J=6.2Hz, 2H), 7.01 (m, 3H), 5.32 (s, 2H), 4.02 (s, 3 H), 3.95 (s, 3H); MS:(M⁺H m/z=423.3).

EXAMPLE 70Dimethyl-{2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolin-4-yl}-amine

To a solution of4-Chloro-2-[4-(1-methyl4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline(135 mg) in tetrahydrofuran (4 mL) was added dimethylamine (2N inmethanol, 0.32 mL), cesium fluoride (5 mg), diisopropyl ethyl amine (62mg) and tetrabutyl ammonium iodide (12 mg). The reaction mixture washeated in a microwave reactor at 180° C. with 100 W of power for 40 min.The reaction mixture was filtered through celite and concentrated.Purification via MPLC biotage chromatography, eluting with 5%methanol/1% ammonium hydroxide/methylene chloride provided the titlecompound (36 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=6.2Hz, 2 H), 8.04(d, J=8.3 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.62 (m, 1H), 7.56 (s, 1H),7.42 (m, 1 H), 7.38 (d, J=9.1 Hz, 2 H), 7.15 (d, J=6.2 Hz, 2H), 7.01 (m,3H), 5.29 (s, 2H), 3.95 (s, 3 H), 3.03 (s, 6H); MS: (M⁺H m/z=436.3).

Preparation 58

N-Methoxy-N-methyl-4-triisopropylsilanyloxymethyl-benzamide

Following the procedure for the preparation of4-benzyloxy-N-methoxy-N-methyl-benzamide but substituting4-Triisopropylsilanyloxymethyl-benzoic acid provided the title compound.MS: (M⁺H m/z=352.1).

Preparation 59

2-Pyridin-4-yl-1-(4-triisopropylsilanyloxymethyl-phenyl)-ethanone

Following the procedure for the preparation of1-(4-Benzyloxy-phenyl)-2-pyridin-4-yl-ethanone but substitutingN-Methoxy-N-methyl-4-triisopropylsilanyloxymethyl-benzamide provided thetitle compound. MS: (M⁺H m/z=384.1).

Preparation 60

4-[1-Methyl-3-(4-triisopropylsilanyloxymethyl-phenyl)-1H-pyrazol-4-yl]-pyridine

Following the procedure for the preparation of4-[3-(4-Benzyloxy-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyridine butsubstituting2-Pyridin-4-yl-1-(4-triisopropylsilanyloxymethyl-phenyl)-ethanoneprovided the title compound. MS: (M⁺H m/z=422.2).

Preparation 61

[4-(l -Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-methanol

To a solution of4-[1-Methyl-3-(4-triisopropylsilanyloxymethyl-phenyl)-1H-pyrazol-4-yl]-pyridine(1.75 g) in THF (16.2 mL) was added TBAF (1.0M THF, 5.2 mL) and thereaction mixture stirred at ambient temperature under inert atmospherefor 1 h. The reaction mixture was poured into saturated sodiumbicarbonate, extracted 3× with chloroform, dried magnesium sulfatefiltered and concentration. Purification via MPLC biotage chromatographyeluting with 2% methanol/0.5% saturated ammonium hydroxide/50% ethylacetate/hexanes provided the title compound (920 mg, 84%). MS: (M⁺Hm/z=266.1).

EXAMPLE 712-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyloxy]-quinoline disuccinic acid

Following the procedure for the preparation of2-{4-[4-Pyridin4-yl-1-(2,212-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoxalinebut substituting[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-methanol andQuinolin-2-ol provided the title compound. ¹H NMR (400 MHz, DMSO) δ 8.42(d, J=5.0 Hz, 2 H), 8.25 (d, J=8.7 Hz, 1H), 8.14 (s, 1H), 7.88 (d, J=7.9Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.66 (t, J=7.1 Hz, 1 H), 7.51 (d, J=7.5Hz, 2 H), 7.40 (m, 3 H), 7.19 (d, J=4.6 Hz, 2H), 7.07 (d, J=8.7 Hz, 1H),5.49 (s, 2H), 2.38 (s, 8 H); MS: (M⁺H m/z=393.1).

Preparation 62

N-((4-(Benzyloxy)phenyl)(tosyl)methyl)formamide

A mixture of 4-methylbenzenesulfinic acid (3.1 g, 19.9 mmol),4-(benzyloxy)benzaldehyde (4.2 g, 19.9 mmol), and formamide (4.5 mL )was heated at 60° C. for 20 h. The mixture was diluted with methanol andstirring was continued for 1 h at rt. The resultant solid was filteredand dried to give 3.81 g (49%) of a white solid. The product was used inthe next step without future purification.

Preparation 63

1-((4-(Benzyloxy)phenyl)isocyanomethylsulfonyl)-4-methylbenzene

To a solution of N-((4-(Benzyloxy)phenyl)(tosyl)methyl)formamide (3.2 g,8.1 mmol) in 43 mL of DME (dimethoxy ethane) at 0° C. was added POCl₃(2.27 mL) followed by the dropwise addition of triethylamine (5.6 mL ).The resultant solution was then stirred at 0° C. for 3 h and finallypoured into cooled water. The precipitate was collected and dried togive 3.3 g of pale yellow solid. MS m/z: 378 [M+1]⁺.

Preparation 64

4-(4-(4-(Benzyloxy)phenyl)oxazol-5-yl)pyridine

A mixture of1-((4-(Benzyloxy)phenyl)isocyanomethylsulfonyl)4-methylbenzene (4.3 g,11.4 mmol), isonicotinaldehyde (1.34 g, 12.5 mmol) and K₂CO₃ (3.15 g,22.8 mmol) in methanol (96 mL ) and DME (30 mL) was heated at reflux for5 h. After removal of solvent, the residue was purified by silica gelchromatography (2:1 hexane/EtOAc) to provide 2.29 g (84%) of a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ: 5.12v (s, 2H), 7.03 (d, 2H), 7.46 (m,6H), 7.56 (d, 2H), 7.61 (d, 2H), 8.02 (s, 1H), 8.58 (d, 2H). MS m/z: 329[M+1]⁺.

Preparation 65

4-(5-(pyridin-4-yl)oxazol-4-yl)phenol

To a solution of 4-(4-(4-(Benzyloxy)phenyl)oxazol-5-yl)pyridine (300 g,0.91 mmol) was added 20% Pd(OH)₂/C (30 mg) and ammonium formate (115 mg,1.83 mmol) in methanol (8 mL ). The solution was heated at 60° C. for 20min. The catalyst was removed by filtration and the filtrate wasconcentrated to give 208 mg (96%) of the title compound. ¹H NMR (400MHz, CDCl₃) δ: 6.92 (m, 2H), 7.46 (m, 2H), 7.57 (d, 2H), 8.02 (s, 1H),8.58 (m, 2H). MS m/z: 239 [M+1]⁺.

EXAMPLE 72 2-((4-(5-(pyridin-4-yl)oxazol-4-yl)phenoxy)methyl)quinoline

To a solution of compound 4-(5-(pyridin4-yl)oxazol4-yl)phenol (90 mg,0.38 mmol) in 1 mL of dry DMF was added CsF (115 mg, 0.76 mmol). Afterstirring for 0.5 h, 2-(chloromethyl)quinoline (67 mg, 0.38 mmol) wasadded and the reaction was heated at 80° C. for 48 h. Upon removal ofDMF under vacuum, the residue was purified by PTLC (1:2 hexane/EtOAc) togive 29 mg (20%) of the title compound as a white solid. ¹H NMR (400MHz, CDCl₃) δ: 5.47 (s, 2H), 7.11 (m, 2H), 7.56 (m, 5H), 7.70 (d, 1H),7.78 (t, 1H), 7.86 (d, 1H), 8.01 (s, 1H), 8.12 (d, 1H), 8.26 (d, 1H),8.57 (d, (2H). MS m/z: 380 [M+1]⁺.

Preparation 66

1-(4-(benzyloxy)phenyl)-2-bromo-2-(pyridin-4-yl)ethanone

To a solution of 1-(4-(benzyloxy)phenyl)-2-(pyridin-4-yl)ethanone (1.39g, 4.58 mmol) in acetic acid was added a solution of bromine (0.72 g,4.58 mmol) in acetic acid (3 mL). After stirring 2 h, the solid wascollected via filtration and washed with acetic acid to provide 1.67 g(96%) of the title compound as a pale yellow solid. ¹H NMR (400 MHz,DMSO) δ: 5.21 (s, 1H), 7.15 (d, 2H), 7.42 (m, 3H), 7.87 (m, 1H), 8.06(d, 2H), 8.77 (m, 1H). MS m/z: 382 [M+1]⁺.

Preparation 67

4-(4-(4-(benzyloxy)phenyl)-2-methyloxazol-5-yl)pyridine

To a mixture of sodium acetate (323 mg, 2.38 mmol) and ammonium acetate(304 mg, 3.95 mmol) in acetic acid (10 mL) was added1-(4-(benzyloxy)phenyl)-2-bromo-2-(pyridin-4-yl)ethanone (302 mg, 0.79mmol). The resulting mixture was then refluxed for 48 h. After removalof the solvent under vacuum, the residue was dissolved in ethyl acetateand the solution was washed with satd NaHCO3. The organic phase wasdried and concentrated in vacuum to give an oil, which was purified viasilica gel chromatography (1:3 EtOAc/n-hexane) to provide 111 mg (41%)of the title compound. ¹H NMR (400 MHz, CDCl₃) δ: 2.58 (s, 3H), 5.15 (s,2H), 7.01 (d, 2H), 7.39 (m, 7H), 7.56 (d, 2H), 8.57 (d, 2H). MS m/z: 343[M+1]⁺.

Preparation 68

4-(2-methyl-5-(pyridin-4-yl)oxazol-4-yl)phenol

4-(4-(4-(Benzyloxy)phenyl)-2-methyloxazol-5-yl)pyridine was hydrogenatedin the presence of ammonium formate and Pd(OH)₂ in methanol for 1 h at50° C. The catalyst was removed via filtration and the filtrate wasconcentrated. The resultant residue was dissolved in methylene chlorideand dried with Na₂SO₄. Evaporation of the solvent gave 69 mg (86%) ofthe title compound as a brown solid. MS m/z: 253.

EXAMPLE 732-((4-(2-methyl-5-(pyridin-4-yl)oxazol-4-yl)phenoxy)methyl)quinoline

To a solution of 4-(2-methyl-5-(pyridin-4-yl)oxazol-4-yl)phenol (21 mg,0.083 mmol) in 2.5 mL of dry DMF was added Cs₂CO₃ (54 mg, 0.17 mmol).After stirring for 0.5 h, 2- (chloromethyl)quinoline (17.8 mg, 0.100mmol) was added and the mixture was stirred at 85° C. for 12 h. Afterremoval of the DMF under vacuum, the residue was purified by PTLC (1:2hexane/EtOAc) to give 13 mg (40%) of the title compound as a pale yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ: 2.54 (s, 3H), 5.41 (s, 2H), 7.06 (m,2H), 7.41 (m, 2H), 7.53 (m, 3H), 7.68 (d, 1H), 7.80 (t, 1H), 7.83 (d,1H), 8.05 (d, 1H), 8.20 (d, 1H), 8.53 (m, 2H). MS m/z: 394 [M+1]⁺.

Preparation 69

4-(4-((quinolin-2-yl)methoxy)phenyl)-3-(pyridin-4-yl)but-3-en-2-one

A mixture of 4-((quinolin-2-yl)methoxy)benzaldehyde (2.5 g, 9.5 mmol),1-(pyridin-4-yl)propan-2-one (1.3 g, 9.5 mmol) and piperidine (162 mg,1.9 mmol) in toluene (50 mL) was heated at reflux for 18 h,concentrated, and the residue chromatographed on silica eluting with agradient of ethyl acetate in hexanes giving impure title substance (2.4g) as a yellow solid which was chromatographed again on silica elutedwith 1% and 2% methanol in dichloromethane containing 0.5% concentratedammonium hydroxide giving a 3:1 mixture of the title substancecontaminated with the pyridyl starting material. Yield 2.0 g, 55%. Thetitle substance appeared to be a 10:1 mixture of two isomers by NMR. ¹HNMR (CDCl₃, 400 mHz, partial) δ 2.35 (s, 3H, major isomer), 2.23 (s, 3H,minor isomer). HPLC-MS 6.09 min, m/e 381 (MH+).

EXAMPLE 742-((4-(3-Methyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline

A mixture of4-(4-((quinolin-2-yl)methoxy)phenyl)-3-(pyridin-4-yl)but-3-en-2-one(1.00 g, 2.60 mmol) and p-toluensulfonylhydrazine (484 mg, 2.6 mmol) inacetic acid (14 mL) was heated at reflux for 10 h. Additionalp-toluenesulfonylhydrazine (242 mg, 0.5 mmol) was added and the mixtureheated at reflux 2 h. The mixture was concentrated, the residuedissolved in dichloromethane and the resulting solution washed withwater (2×25 mL), dried and concentrated. The residue was chromatographedon silica eluted with 1%, 2%, and 3% methanol in dichloromethanecontaining 0.5% concentrated ammonium hydroxide giving a solid which wastriturated with ether and dried. Yield 293 mg, 29%. ¹H NMR (CDCl₃, 400mHz) δ 8.51 (m, 2H), 8.18 (d, 1H, J=8.7 Hz), 8.06 (d, 1H, J=7.9 Hz),7.81 (d, 1H, J=8.3 Hz), 7.72 (m, 1H), 7.64 (d, 1H, J=8.3 Hz), 7.54 (m,1H), 7.24 (m, 2H), 7.13 (m, 2H), 6.96 (m, 2H), 5.36 (s, 2H), 2.33 (s,3H). HPLC-MS (system 1) 4.65 min, m/e 393 (MH+).

EXAMPLE 752-((4-(1,3-dimethyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline

A solution of2-((4-(3-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline(150 mg, 0.38 mmol) in anhydrous dimethylformamide (2 mL) was treated at0° C. with sodium hydride dispersion (30 mg, 0.76 mmol of 60% NaH inoil) followed after 20 min with methyl iodide (54 mg, 0.38 mmol), andthe stirred mixture was allowed to warm to RT overnight. Water was addedand the mixture extracted with dichloromethane (3×20 mL). The organiclayer was dried, concentrated, and the residue chromatographed on silicaeluted with an ethyl acetate-hexane gradient containing 1%triethylamine, giving fractions containing two isomeric substances. Theless polar isomer (18 mg) was thus obtained (methylation regiochemistrytentatively assigned by NMR). ¹H NMR (CDCl₃, 400 mHz) δ 8.41 (m, 2H),8.21 (d, 1H, J=8.7 Hz), 8.07 (d, 1H, J=8.3 Hz), 7.84 (d, 1H, J=9.5 Hz),7.74 (ddd, 1H), 7.67 (d, 1H, J=8.3 Hz), 7.55 (ddd, 1H), 7.12 (m, 2H),7.05 (m, 2H), 7.0 (m, 2H), 5.40 (s, 2H), 3.71 (s, 3H), 2.37 (s, 3H).HPLC-MS 4.81 min, m/e 407 (MH+).

EXAMPLE 762-((4-(1,5-dimethyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinoline

The more polar fractions obtained from the sodium hydride/methyl iodidealkylation of2-((4-(3-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinolinegave 26 mg of impure title substance which was recrystallized from 10:1ethyl acetate-hexanes giving isomerically pure material whosemethylation regiochemistry was tentatively assigned by NMR. ¹H NMR(CDCl₃, 400 mHz) δ 8.51 (m, 2H), 8.17 (d, 1H, J=8.7 Hz), 8.05 (d, 1H,J=8.3 Hz), 7.85 (d, 1H, J=8.3 Hz), 7.72 (ddd, 1H), 7.65 (d, 1H, J=8.7Hz), 7.53 (t, 1H, J=7.5 Hz), 7.27 (m, 2H), 7.12-7.11 (m, 2H), 6.93 (m,2H), 5.36 (s, 2H), 3.87 (s, 3H), 2.30 (s, 3H), HPLC-MS 4.78 min, m/e 407(MH+).

Preparation 69a

1-(quinolin-2-yl)ethanol

A solution of methylmagnesium bromide (17.6 mL of 1.4 M in toluene, 24.7mmol) was added at <10° C. to a solution of quinoline-2-carboxaldehyde(3.0 g, 19 mmol) in anhydrous tetrahydrofuran (50 mL). The mixture wasstirred at RT for 1 h and poured into saturated aqueous ammoniumchloride (100 mL), and the resulting mixture was extracted with ethylacetate (3×150 mL). The extracts were dried, concentrated, and theresidue chromatographed on silica eluted with 30% and 40% ethylacetate-hexanes giving a yellow solid. Yield 2.46 g, 75%. ¹H NMR (CDCl₃,400 mHz) δ 8.15 (d, 1H, J=8.7 Hz), 8.07 (d, 1H, J=8.7 Hz), 7.81 (dd, 1H,J=1, 8 Hz), 7.71 (ddd, 1H, J=1, 7, 8.5 Hz), 7.51 (ddd, 1H, J=1, 7, 8.3Hz), 7.33 (d, 1H, J=8.3 Hz), 5.07-4.99 (m, 2H), 1.56 (d, 3H, J=6.2 Hz).

EXAMPLE 772-(1-(4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)ethyl)quinoline

A mixture of 4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenol (75 mg,0.30 mmol) and 1-(quinolin-2-yl)ethanol (78 mg, 0.45 mmol) in p-dioxane(2 mL) was treated sequentially at RT with triphenylphosphine (126 mg,0.48 mmol) and di-t-butyldiazodicarboxylate (110 mg, 0.48 mmol) and themixture was heated at 60° C. for 4 h. Aqueous 2N NaOH was added and themixture extracted with dichloromethane. The organic layers were dried,concentrated, and the residue purified on silica gel eluted with agradient of ethyl acetate-hexanes giving a yellow solid. Yield 36 mg,29%. ¹H NMR (CDCl₃, 400 mHz) δ 8.40 (m, 2H), 8.10 (d, 1H, J=8.7 Hz),8.06 (d, 1H, J=7.5 Hz), 7.77 (d, 1H, J=8.3 Hz), 7.71 (ddd, 1H), 7.55 (d,1H, J=8.3 Hz), 7.53-7.49 (m, 2H), 7.25 (m, 2H), 7.10 (m, 2H), 6.88 (m,2H), 5.59 (q, 1H, J=6.6 Hz), 3.91 (s, 3H), 1.75 (d, 3H, J=6.6 Hz).HPLC-MS (system 1) 4.73 min, m/e 407 (MH+).

Preparation 70

2-((4-(2-(pyridin-4-yl)ethynyl)phenoxy)methyl)quinoline

A mixture of 4-(2-(pyridin-4-yl)ethynyl)phenol (335 mg, 1.72 mmol),2-(chloromethyl)quinoline hydrochloride (385 mg, 1.8 mmol), and cesiumcarbonate (2.2 g, 6.87 mmol) was stirred in dimethylformamide (8 mL) at65° C. for 3 h. Water (20 mL) was added and the mixture was extractedwith dichloromethane (3×15 mL). The organic layers were dried,concentrated, and the residue chromatographed on silica eluted with agradient of 10% to 80% ethyl acetate-hexanes giving 450 mg (78%) of ayellow solid. ¹H NMR (CDCl₃, 400 mHz) δ 8.56 (m, 2H), 8.20 (d, 1H, J=8.7Hz), 8.08 (d, 1H, J=8.3 Hz), 7.82 (d, 1H, J=7.9 Hz), 7.74 (ddd, 1H,J=8.4, 7, 1Hz), 7.63 (d, 1H, J=8.7 Hz), 7.55 (ddd, 1H, J=8, 7, 1 Hz),7.47 (m, 2H), 7.35 (m, 2H), 7.01 (m, 2H), 5.41 (s, 2H). MS (AP+) m/e 337(MH+).

Preparation 71

4-(2-(pyridin-4-yl)ethynyl)phenol

Boron tribromide (1M in dichloromethane, 9.7 mL, 9.7 mmol) was added at0° C. to a solution of 4-(2-(4-methoxyphenyl)ethynyl)pyridine (810 mg,3.88 mmol) in dichloromethane (10 mL) and the mixture was stirred at RTfor 5 h. Aqueous 1 N sodium hydroxide (20 mL) was added and after 40 minthe pH was brought between 7 and 8 by addition of 1 N HCl. The resultingmixture was extracted with 4:1 dichloromethane:2-propanol (3×30 mL). Theorganic layers were dried, concentrated and evaporated and the residuechromatographed on silica in a gradient from 25% to 80% ethylacetate-hexanes giving a brown solid. Yield 450 mg, 60%. ¹H NMR (CDCl₃containing CD₃OD, 400 mHz) δ 8.50 (br, 2H), 7.38 (br, 2H), 7.37 (d, 2H,J=8.7 Hz), 6.77 (d, 2H, J=8.7 Hz), 3.11 (br, 2H, OH+H2O). MS (AP+) m/e196 (MH+).

Preparation 72

4-(2-(4-methoxyphenyl)ethynyl)pyridine

A mixture of 4-methoxyphenylacetylene (2.86 g, 21.7 mmol),4-iodopyridine (4.44 g, 21.7 mmol), cuprous iodide (206 mg, 1.08 mmol),bis(triphenylphosphine)palladium(II) dichloride (758 mg, 1.08 mmol) intetrahydrofuran (40 mL) and triethylamine (20 mL) was heated at refluxfor 2 h. The mixture was filtered, concentrated, and the residuechromaptographed on silica in 1:1 ethyl acetate-hexanes giving 2.45 g(54%) of a yellow solid. ¹H NMR (CDCl₃, 400 mHz) δ 9.2 (very broad, 2H),7.57 (br, 2H), 7.48 (d, 2H, J=8.7 Hz), 6.88 (d, 2H, J=8.7 Hz), 3.82 (s,3H). MS (AP+) m/e 210 (MH+).

EXAMPLE 782-((4-(5-(pyridin-4-yl)-1,2,3-triazol-4-yl)phenoxy)methyl)quinoline

Trimethylsilylazide (730 mg, 6.4 mmol) and2-((4-(2-(pyridin-4-yl)ethynyl)phenoxy)methyl)quinoline (360 mg) werecombined in a screw cap sealed tube and heated behind a safety shield ina 150° C. bath for 72 h. The mixture was concentrated and the yellowresidue triturated with ether (2×10 mL) leaving a yellow solid (346 mg)which was chromatographed on silica eluted with a gradient of 0.5%-2%methanol in dichloromethane giving a yellow solid (210 mg,52%). ¹H NMR(CDCl₃ with a drop of CD₃OD, 400 mHz) δ 8.54 (d, 2H, J=6.2 Hz), 8.23 (d,1H, J=8.7 Hz), 8.07 (d, 1H, J=8.7 Hz), 7.84 (d, 1H, J=7.9 Hz), 7.74(ddd, 1H, J=8.4, 7, 1Hz), 7.69 (d, 1H, J=8.7 Hz), 7.63 (d, 2H, J=6.2Hz), 7.56 (ddd, 1H), 7.41 (m, 2H), 7.09 (m, 2H), 5.41 (s, 2H). MS (AP+)m/e 380 (MH+).

Preparation 73

4-(2-methyl-5-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)phenol

A solution of4-(5-(4-methoxyphenyl)-2-methyl-2H-1,2,3-triazol-4-yl)pyridine (203 mg,0.76 mmol) in dichloromethane (5 mL) was treated at 0° C. with borontribromide (2.3 mL of 1M in dichloromethane) and the mixture stirred 18h at RT. Methanol (3 mL) was added and the mixture was concentrated andextracted using dichloromethane and aqueous sodium bicarbonate. Theorganic extracts were dried and concentrated giving a yellow solid whichwas chromatographed on silica (gradient of 0.5%-3% methanol indichloromethane) giving two substances. The more polar substance (88 mg)was assigned 4-(2-methyl-5-(pyridin4-yl)-2H-1,2,3-triazol-4-yl)phenol.¹H NMR (CDCl₃, 400 mHz, partial) δ 8.57 (br, 2H), 7.59 (d, 2H, J=5.2Hz), 7.32 (m, 2H), 6.90 (m, 2H), 4.26 (s, 3H). HPLC-MS (system 1) 3.96min, m/e 253 (MH+). The less polar substance (80 mg) was assigned to bethe corresponding boronate as it was found to convert on treatment withaqueous NaOH to the less polar substance.

Preparation 74

4-(5-(4-methoxyphenyl)-2-methyl-2H-1,2,3-triazol-4-yl)pyridine,4-(5-(4-methoxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridine, and4-(5-(4-methoxyphenyl)-3-methyl-3H-1,2,3-triazol-4-yl)pyridine

Sodium hydride (240 mg of 60% oil dispersion, 6.0 mmol) was added to asolution of 4-(5-(4-methoxyphenyl)-1,2,3-triazol-4-yl)pyridine (755 mg,3.0 mmol) in dimethylformamide (10 mL) at 0° C. and the mixture wasstirred 30 min. Methyl iodide (425 mg) was added and the mixture wasstirred at 0° C. for 2.5 h, quenched with water (20 mL), and extractedwith dichloromethane (3×20 mL). The organic layers were dried overmagnesium sulfate and concentrated. The residue was chromatographed onsilica eluted with a gradient of 50% to 100% ethyl acetate-hexanesproviding three isomeric substances of increasing polarity. Each showeda mass of m/e 267 (MH+) by HPLC-MS. Each structure was assigned bysingle crystal X-ray on crystals grown from either ethyl acetate oracetonitrile. The least polar substance (454 mg of yellow solid),4-(5-(4-methoxyphenyl)-2-methyl-2H-1,2,3-triazol-4-yl)pyridine, ¹H NMR(CDCl₃, 400 mHz) δ 8.59 (br, 2H), 7.52 (br, 2H), 7.41 (m, 2H), 6.93 (m,2H), 4.26 (s, 3H), 3.84 (s, 3H). The middle-polarity substance (235 mgyellow solid),4-(5-(4-methoxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridine, ¹H NMR(CDCl₃, 400 mHz) δ 8.49 (d, 2H, J=6.22), 7.52 (m, 2H), 7.24 (m, 2H),7.06 (m, 2H), 3.91 (s, 3H), 3.89 (s, 3H). The most polar substance (50mg yellow solid),4-(5-(4-methoxyphenyl)-3-methyl-3H-1,2,3-triazol-4-yl)pyridine, ¹H NMR(CDCl₃, 400 mHz) δ 8.59 (br, 2H), 7.52 (br, 2H), 7.41 (m, 2H), 6.93 (m,2H), 4.26 (s, 3H), 3.84 (s, 3H).

Preparation 75

4-(5-(4-methoxyphenyl)-1,2,3-triazol-4-yl)pyridine

4-(2-(4-methoxyphenyl)ethynyl)pyridine (1.48 g, 7.1 mmol) andtrimethylsilylazide (2.5 g, 21.3 mmol) were combined in a sealed tubewhich was heated 48 h in a 150° C. oil bath. The mixture waschromatographed on silica using an ethyl acetate-hexanes gradient givinga yellow solid (950 mg, 53%). ¹H NMR (CDCl₃, 400 mHz) δ 8.50 (d, 2H,J=5.8 Hz), 7.60 (d, 2H, J=5.8 Hz), 7.36 (d, 2H, J=8.7 Hz), 6.92 (d, 2H,J=8.7 Hz), 3.81 (s, 3H), 2.80 (br, 1H). MS (AP+) m/e 253 (MH+).

EXAMPLE 792-((4-(2-methyl-5-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)phenoxy)methyl)quinoline

A mixture of 4-(2-methyl-5-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)phenol(80 mg, 0.32 mmol), 2-(chloromethyl)quinoline hydrochloride (71 mg, 0.33mg), and cesium carbonate (414 mg, 1.27 mmol) in dimethylformamide washeated at 65° C. for 20 h, filtered, the filtrate concentrated andchromatographed on silica eluted with ethyl acetate-hexanes providingmaterial containing starting phenol. This was dissolved in ethylacetate, washed with aqueous NaOH, dried and concentrated giving acolorless solid (100 mg, 80%). ¹H NMR (CDCl₃, 400 mHz) δ 8.56 (d, 2H,J=6.2 Hz), 8.24 (d,1H, J=8.3 Hz), 8.12 (d, 1H, J=8.3 Hz), 7.85 (d, 1H,J=8.3 Hz), 7.75 (ddd, 1H, J=8.5, 7, 1.6 Hz), 7.70 (d, 1H, J=8.7 Hz),7.65 (d, 2H, J=6.2 Hz), 7.57 (m, 1H), 7.41 (m, 2H), 7.08 (m, 2H), 5.45(s, 2H), 4.27 (s, 3H). MS (AP+) m/e 394 (MH+).

Preparation 76

4-(3-methyl-5-(pyridin-4-yl)-3H-1,2,3-triazol-4-yl)phenol

A solution of4-(5-(4-methoxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridine (170 mg,0.64 mmol) in dichloromethane (5 mL) was treated at RT With borontribromide (1.27 mL of 1M in dichloromethane) and the mixture wasstirred overnight. Aqueous 1N NaOH (10 mL) was added, and after beingstirred 1 h the mixture was extracted with dichloromethane (20 mL). Theaqueous layer was acidified to pH 7 with 2N HCl, and extracted withethyl acetate (2×15 mL). The extracts were dried with sodium sulfate andconcentrated giving a yellow solid (142 mg, 88%). ¹H NMR (CDCl₃, 400mHz) δ ¹H NMR (CDCl₃, 400 mHz) δ 8.39 (d, 2H, J=5-6 Hz), 7.49 (d, 2H,J=5-6 Hz), 7.09 (d, 2H, J=8.7 Hz), 6.95 (d, 2H, J=8.7 Hz), 3.87 (s, 3H).MS (AP−) 351 (M−H).

EXAMPLE 80 2-((4-(3-methyl-5-(pyridin-4-yl)-3H-1,2,3-triazol-4-yl)phenoxy)methyl)quinoline

A mixture of 4-(3-methyl-5-(pyridin-4-yl)-3H-1,2,3-triazol-4-yl)phenol(88 mg, 0.35 mmol), 2-(chloromethyl)quinoline hydrochloride (82 mg, 0.38mmol), and cesium carbonate (455 mg, 1.4 mmol) in dimethylformamide wasstirred at 65° C. for 20 h, filtered, and concentrated. The residue waschromatographed on silica eluting with a gradient of 50% to 100% ethylacetate in hexanes giving a light yellow solid (100 mg, 73%). ¹H NMR(CDCl₃, 400 mHz) δ 8.48 (d, 2H, J=6.2 Hz), 8.24 (d, 1H, J=8.3 Hz), 8.09(d, 1H, J=8.3 HZ), 7.85 (d, 1H, J=7.9 Hz), 7.76 (ddd, 1H, J=8.5, 7,1Hz), 7.70 (d, 1H, J=8.7 Hz), 7.57 (m, 1H), 7.54 (m, 2H), 7.24 (m, 2H),7.20 (m, 2H). 5.46 (s, 2H), 3.90 (s, 3H). MS (AP+) m/e 394 (MH+).

Preparation 77

4-(1-(pyridin-4-yl)-1H-imidazol-2-yl)phenol

According to the procedure for preparation of4-(3-methyl-5-(pyridin-4-yl)-3H-1,2,3-triazol-4-yl)phenol, except that4:1 dichloromethane:2-propanol was used in place of ethyl acetate toextract the product, 4-(2-(4-methoxyphenyl)-1H-imidazol-1-yl)pyridine(125 mg, 0.5 mmol) was treated with 1.25 mmol of boron tribromide togive 90 mg of a colorless solid. ¹H NMR (CDCl₃, 400 mHz) δ 8.52 (d, 2H,J=6 Hz), 7.14 (m, 2H), 7.11-7.08 (m, 4H), 6.79 (m, 2H), 2.94 (br, 1 H).

Preparation 78

4-(2-(4-methoxyphenyl)-1H-imidazol-1-yl)pyridine

Phosphorus pentachloride (572 mg, 2.75 mmol) was added to a mixture of4-methoxy-N-(pyridin-4-yl)benzamide (626 mg, 2.75 mmol) in phosphorusoxychloride (3 mL) and the mixture was heated a 105° C. oil bath for 4h. The mixture was concentrated to dryness. To the residue was added2,2-dimethoxyethylamine (3.1 g) in methanol, and the mixture was stirredat RT. After more than one hour the mixture was partially concentratedto remove most of the methanol, stirred at RT overnight and concentratedto dryness. Isopropyl alcohol (10 mL) and conc. HCl (15 mL) were addedand the mixture was heated at 80° C. for 24 h. Solid sodium bicarbonatewas added to bring the pH to 7-8, and the mixture was extracted withdichloromethane (3×50 mL) which was dried (sodium sulfate) andconcentrated. Chromatography on silica eluted with 25% to 100% ethylacetate-hexanes gave 130 mg (20%) of a yellow solid. ¹H NMR (CDCl₃, 400mHz) δ 8.55 (d, 2H, J=6 Hz), 7.22 (d, 2H, J=9Hz), 7.17 (s, 1H), 7.12 (s,1H), 7.05 (d, 2H, J=6 Hz), 6.75 (d, 2H, J=9 Hz), 3.72 (s, 3H).

Preparation 79

4-methoxy-N-(pyridin-4-yl)benzamide

4-Aminopyridine (1.94 g, 20.6 mmol) was added to a solution of p-anisoylchloride (3.5 g, 20.6 mmol) and triethylamine (8.6 mL, 62 mmol) indichloromethane (100 mL) at 0° C. The mixture was stirred 3 h at RT, andthen extracted successively with 1N NaOH, water and brine, dried oversodium sulfate, and concentrated. Chromatography on silica (gradient of30% to 100% ethyl acetate-hexanes) gave 3.8 g (81%) of a colorlesssolid. ¹H NMR (CDCl₃, 400 mHz) δ 8.49 (m, 2H), 8.19 (br, 1H), 7.85 (m,2H), 7.59 (m, 2H), 6.95 (m, 2H), 3.85 (s, 3H), MS (AP+) 229 (MH+).

EXAMPLE 812-((4-(1-(pyridin-4-yl)-1H-imidazol-2-yl)phenoxy)methyl)quinoline

According to the procedure for preparation of2-((4-(3-methyl-5-(pyridin-4-yl)-3H-1,2,3-triazol-4-yl)phenoxy)methyl)quinoline,4-(1-(pyridin-4-yl)-1H-imidazol-2-yl)phenol (90 mg),2-(chloromethyl)quinoline hydrochloride (81 mg) and cesium carbonate(495 mg) gave 120 mg as an off-white solid (84%). ¹H NMR (CDCl₃, 400mHz) δ 8.59 (m, 2H), 8.16 (d, 1H, J =8.3 Hz), 8.04 (d, 1H, J=8.3 Hz),7.79 (d, 1H, J=7.9 Hz), 7.70 (ddd, 1H), 7.60 (d, 1H, J=8.3 Hz), 7.52(ddd, 1H), 7.28 (m, 2H), 7.22 (d, 1H, J=1 Hz), 7.15 (d, 1H, J=1 Hz),7.11 (m, 2H), 6.94 (m, 2H), 5.34 (s, 2H). HPLC-MS (system 1) 4.53 min,m/e 379 (MH+).

Preparation 80

4-(1-(4-methoxyphenyl)-1H-imidazol-5-yl)pyridine

4-Methoxyaniline (2.46 g, 20 mmol) and pyridine-4-carboxaldehyde (1.9mL, 10 mmol) in toluene (110 mL) in a flask attached to a Dean-Starktrap and reflux condensor was heated at reflux. After 40 hours, thereaction was complete by infrared spectral analysis and mass spectralanalysis. The toluene was removed via distillation through theDean-Stark sidearm, the residue was dissolved in methanol (100 mL) andca. ½ of the crude imine (ca. 10 mmol, 50 mL of methanol solution) wasdiluted with methanol (20 mL) and 1,2-dimethoxyethane (20 mL). Thesolution was then treated with potassium carbonate (2.76 g, 20 mmol) andtosylmethylisocyanide (TOSMIC, 2.93 g, 15 mmol) and was heated at refluxfor 3 hours. After cooling to room temperature, the solvent was removedin vacuo, and the residue was dissolved in methylene chloride and waswashed with brine. The brine layer was extracted with methylene chlorideand the combined organic layers were dried (MgSO₄), were filtered, andwere concentrated in vacuo. The residue was purified by silica gelchromatography with ethyl acetate—hexanes—methanol (80:20:0 to 76:19:5)to afford 1.4 g (56% yield) of the title compound; diagnostic ¹³C NMRsignals (100 MHz, CDCl₃) δ 160.039, 150.161, 141.009, 137.240, 130.839,129.179, 127.287, 121.597, 115.106, 55.801; MS (AP/Cl) 252.4 (M⁺H)+.

Preparation 81

4-(1-(4-(benzyloxy)phenyl)-1H-imidazol-5-yl)pyridine

The title compound was prepared using the method described forPreparation 80, substituting 4-benzyloxyaniline for 4-methoxyaniline,and afforded 4-(1-(4-(benzyloxy)phenyl)-1H-imidazol-5-yl)pyridine in 54%yield; diagnostic ¹³C NMR signals (100 MHz, CDCl₃) δ 159.195, 150.132,141.001, 137.263, 136.403, 130.892, 130.735, 129.389, 128.932, 128.521,127.751, 127.317, 121.627, 116.078, 70.637; MS (AP/Cl) 328.4 (M+H)+.

Preparation 82

4-(1-(4-methoxyphenyl)-2-methyl-1H-imidazol-5-yl)pyridine

A solution of diisopropyl amine (0.51 mL, 3.6 mmol) in tetrahydrofuran(12 mL) at −20° C., was treated with n-butyl lithium (2.5 M in hexanes,1.45 mL, 3.6 mmol) and the solution was stirred for 10 minutes. Asolution of Preparation 80(4-(1-(4-methoxyphenyl)-1H-imidazol-5-yl)pyridine, 730 mg, 2.9 mmol) intetrahydrofuran was added and the solution became dark orange. Thesolution was stirred for 30 minutes as the temperature was allowed torise to 0° C. After cooling to −20° C., methyl iodide (0.54 mL, 8.7mmol) in tetrahydrofuran (12 mL) was added and the solution was stirredfor 30 min at −20° C. and for 2 hr at 23° C. The solvent was removed invacuo, the residue was diluted with brine and was extracted with ethylacetate. The organic layer was then dried (MgSO₄), was filtered, and wasconcentrated in vacuo. The residue was purified by silica gelchromatography using ethyl acetate-hexanes-methanol (63:32:5 to72:18:10) to afford 555 mg (72% yield) of the title compound; diagnostic¹³C NMR signals (100 MHz, CDCl₃) δ 160.144, 150.034, 149.197, 137.749,131.265, 129.463, 128.985, 128.828, 120.849, 115.233, 55.78, 14.203; MS(AP/Cl) 266.4 (M+H)+.

Preparation 83

4-(2-ethyl-1-(4-methoxyphenyl)-1H-imidazol-5-yl)pyridine

The title compound was prepared using the method described forPreparation 82 with ethyl iodide used in the place of methyl iodide andafforded 83% yield of4-(2-ethyl-1-(4-methoxyphenyl)-1H-imidazol-5-yl)pyridine; diagnostic ¹³CNMR signals (100 MHz, CDCl₃) δ 160.144, 150.147, 149.990, 137.786,129.239, 129.037, 128.992, 121.597, 120.909, 115.181,55.771,21.097,12.348; MS (AP/Cl) 280.5 (M+H)+.

Preparation 84

4-(5-(pyridin-4-yl)-1H-imidazol-1-yl)phenol

A solution of Preparation 81(4-(1-(4-(benzyloxy)phenyl)-1H-imidazol-5-yl)pyridine, 2 g, 6.1 mmol)and anisole (13 mL, 122 mmol) in trifluoracetic acid (50 mL) was heatedat 75° C. for 24 h. The solvent was removed in vacuo and the residue waspurified via silica gel chromatography with chloroform-methanol-ammoniumhydroxide (94:5:1) to afford 1.27 g (88%) of the title compound;diagnostic ¹³C NMR signals (100 MHz, CDCl₃) δ 158.402, 149.145, 141.061,138.018, 120.600, 129.822, 127.482, 127.370, 121.933, 116.497; MS(AP/Cl) 238.3 (M+H)+.

Preparation 85

4-(2-methyl-5-(pyridin-4-yl)-1H-imidazol-1-yl)phenol

A solution of boron tribromide (1 M in methylene chloride, 2.1 mL, 2.1mmol) was added dropwise to a solution of Preparation 82(4-(1-(4-methoxyphenyl)-2-methyl-1H-imidazol-5-yl)pyridine, 220 mg, 0.83mmol) in methylene chloride (5 mL) at 0° C. After stirring at 23° C. for24 h, aqueous sodium hydroxide solution (1 N, 15 mL) was added and themixture was stirred at 23° C. for 1 h. The pH was adjusted to 7 by theaddition of aqueous hydrochloric acid (1N), the mixture was extractedwith methylene chloride/isopropanol (4:1, 3×30 mL), the combined organiclayers were dried (MgSO₄), were filtered, and were concentrated invacuo. The residue was purified by silica gel chromatography usingchloroform-methanol (20:1 to 10:1) to afford 150 mg (72% yield ) of thetitle compound; diagnostic ¹³C NMR signals (100 MHz, CDCl₃) δ 159.337,149.548, 149.302, 138.302, 131.131, 128.760, 128.170, 127.310, 121.163,117.237, 13.881; MS (AP/Cl) 252.4 (M+H)+.

Preparation 86

4-(2-ethyl-5-(pyridin-4-yl)-1H-imidazol-1-yl)phenol

The title compound was prepared using Preparation 4 as the startingmaterial and the method for Preparation 85. This yielded4-(2-ethyl-5-(pyridin-4-yl)-1H-imidazol-1-yl)phenol in 70% yield;diagnostic ¹³C NMR signals (100 MHz, CD₃OD/CDCl₃) δ 158.574, 149.182,149.002, 138.511, 130.877, 128.895, 128.200, 127.340, 121.253, 116.692,20.656, 12.020; MS (AP/Cl) 266.4 (M+H)+.

EXAMPLE 822-((4-(5-(pyridin-4-yl)-1H-imidazol-1-yl)phenoxy)methyl)quinoline

A mixture of Preparation 84(4-(5-(pyridin-4-yl)-1H-imidazol-1-yl)phenol, 95 mg, 0.4 mmol),2-chloromethylquinoline hydrochloride (128 mg, 0.6 mmol), and cesiumcarbonate (391 mg, 1.2 mmol) in dimethylsulfoxide (2 mL) was stirred at23° C. for 24 h. The mixture was diluted with ethyl acetate/n-butanol(100 mL/5 mL), was washed with water and then brine, and the organiclayer was dried (MgSO₄), was filtered, and was concentrated in vacuo.The residue was purified by silica gel chromatography usingchloroform/methanol (50:1) to afford 150 mg (99% yield) of the titlecompound; diagnostic ¹³C NMR signals (100 MHz, CDCl₃) δ 158.940,157.116, 149.990, 147.836, 141.054, 137.405, 130.989, 130.204, 129.650,129.239, 127.953, 127.871, 127.392, 127.011, 121.627, 119.324, 116.198,71.990; MS (AP/Cl) 379.4 (M+H)+.

EXAMPLE 832-((4-(2-methyl-5-(pyridin-4-yl)-1H-imidazol-1-yl)phenoxy)methyl)quinoline

The title compound was prepared using Preparation 85 and the methoddescribed in Example 82; 88% yield; diagnostic ¹³C NMR signals (100 MHz,CDCl₃) δ 159.060, 157.078, 150.004, 147.836, 137.689, 137.397, 130.204,129.934, 129.239, 128.962, 127.968, 127.871, 127.385, 127.011, 120.886,119.354, 116.273, 71.975, 14.225; MS (AP/Cl) 393.49 (M+H)+.

EXAMPLE 842-((4-(2-ethyl-5-(pyridin-4-yl)-1H-imidazol-1-yl)phenoxy)methyl)quinoline

The title compound was prepared using Preparation 86 and the methoddescribed in Example 82; 92% yield; diagnostic ¹³C NMR signals (100 MHz,CDCl₃) δ 159.090, 157.078, 150.147, 149.930, 147.836, 137.734, 137.405,130.211, 129.680, 129.232, 129.127, 128.970, 127.968, 127.886, 127.392,127.018, 120.961, 119.354, 116.243, 71.968, 21.090, 12.333; MS (AP/Cl)407.5 (M+H)+.

Preparation 87

N-(4-methoxyphenyl)isonicotinamide

A solution of p-anisidine (2.46 g, 20 mmol) and triethylamine (13.9 mL,100 mmol) in ethyl acetate (200 mL) was treated with isonicotinic acid(2.46 g, 20 mmol) followed by 1-propanephosphonic acid cyclic anhydride(50% in ethyl acetate, 15.1 mL, 24 mmol). After stirring at 23° C. for 4h, the reaction mixture was diluted with ethyl acetate, was washed withwater and with brine, and the organic layer was dried (MgSO₄), wasfiltered, and was concentrated in vacuo. Purification by silica gelchromatography with chloroform-methanol (40:1) gave 4 g (88% yield) ofthe title compound; diagnostic ¹³C NMR signals (100 MHz, CD₃OD/CDCl₃) δ164.825, 157.213, 149.758, 143.349, 130.989, 123.085, 122.068, 55.285;MS (AP/Cl) 229.3 (M+H)+.

Preparation 88

4-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)pyridine

Preparation 87 (N-(4-methoxyphenyl)isonicotinamide, 1 g, 4.39 mmol) wasdissolved in phosphorous oxychloride (POCl₃) (5 mL) then phosphorouspentachloride (913 mg, 4.39 mmol) was added. The mixture was heated at120° C. for 4 h. The POCl₃ was removed in vacuo, aminoacetaldehydedimethyl acetal (9.5 mL, 87.8 mmol) and isopropanol (10 mL) were added,and the mixture was stirred at 23° C. for ca. 16 h. The reaction mixturewas concentrated in vacuo and concentrated hydrochloric acid (36.5%, 25mL) in isopropanol (15 mL) was added. The reaction mixture was heated at90° C. for 24 h. After cooling to 23° C., aqueous sodium hydroxide (1N)and aqueous sodium bicarbonate were added to obtain pH=8. The mixturewas extracted with methylene chloride, was dried (MgSO₄), and wasfiltered and concentrated in vacuo. The residue was purified by silicagel chromatography with ethyl acetate/hexanes/methanol (80:20:0 to76:19:5) to afford 811 mg (74% yield) of the title compound; diagnostic¹³C NMR signals (100 MHz, CDCl₃) δ 160.069, 149.952, 144.142, 137.853,131.004, 129.882, 127.414, 124.977, 122.195, 115.114, 55.808; MS (AP/Cl)252.4 (M+H)+.

Preparation 89

4-(2-(pyridin-4-yl)-1H-imidazol-1-yl)phenol

The title compound was prepared using the method outlined in Preparation85 with the substitution of Preparation 88 for Preparation 82; 86%yield; diagnostic ¹³C NMR signals (100 MHz, CD₃OD/CDCl₃) δ 158.372,149.145, 143.641, 138.257, 129.232, 128.985, 127.347, 125.418, 122.666,116.505; MS (AP/Cl) 238.4 (M+H)+.

EXAMPLE 85

2-((4-(2-(pyridin-4-yl)-1H-imidazol-1-yl)phenoxy)methyl)quinoline

The title compound was prepared using the method outlined in Example 82with the substitution of Preparation 89 for Preparation 84; 98% yield;diagnostic ¹³C NMR signals (100 MHz, CDCl₃) δ 158.948, 157.108, 149.847,147.814, 137.868, 137.420, 131.445, 130.226, 129.942, 127.968, 127.871,127.534, 127.026, 124.954, 122.247, 119.339, 116.190, 71.968; MS (AP/Cl)379.4 (M+H)+.

The invention described and claimed herein is not to be limited in scopeby the specific embodiments herein disclosed, since these embodimentsare intended as illustrations of several aspects of the invention. Anyequivalent embodiments are intended to be within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art from the foregoing description. Such modifications are alsointended to fall within the scope of the appended claims.

1. A compound of formula I or a pharmaceutical acceptable salt thereof,

wherein Z is

R¹ is each independently selected from a group consisting of hydrogen orhalogen; R² is hydrogen or C₁ to C₈ alkyl; HET¹ is 2,3-pyrazole whichmay be optionally substituted with at least one R⁴; R⁴ is C₁ to C₈alkyl, C₃ to C₈ haloalkyl, or a C₁ to C₈ alkyl substituted with asubstituent selected from a group consisting of —OR⁸ and —NR⁸R⁸, whereinR⁸ is independently selected from a group consisting of hydrogen and C₁to C₈ alkyl; HET² is a 4-pyridyl, which may be optionally substitutedwith at least one R⁵; R⁵ is independently selected from a groupconsisting of halogen, C₁ to C₈ alkyl and —NR⁷R⁷; B¹ and B² are adjacentatoms in Het¹ and are both carbon; bond j is a covalent bond between Zand B²; bond k is a bond in Het¹ between B¹ and B²; X is oxygen orC(R²)₂ and X¹ is C(R²)₂; Y is carbon substituted with R⁸; wherein eachR⁶ is independently selected from a group consisting of hydrogen,halogen, hydroxyl, C₁ to C₈ alkoxy and NR⁷R⁷; wherein each R⁷ isindependently selected from a group consisting of hydrogen andC₁-C₈alkyl; p is 1, 2 or
 3. 2. The compound of claim 1 or apharmaceutical acceptable salt thereof, wherein the compound of formulaI has the following structure:


3. The compound of claim 1, or a pharmaceutical acceptable salt thereof,wherein the compound of formula I has the following structure:


4. The compound of claim 1, or a pharmaceutical acceptable salt thereofwherein X¹ is C(R²)₂ and X is oxygen.
 5. The compound of claim 1,wherein said compound is selected from a group consisting of:2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline;2-[4-(2-Methyl-4-pyridin4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline;2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline;2-[4-(2-Ethyl-4-pyridin4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline;2-[4-(1-Ethyl-4-pyridin4-yl-1H-pyrazol-3-yl )-phenoxymethyl]-quinoline;Dimethyl-(2-{4-pyridin4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-ethyl)-amine;Dimethyl-(2-{4-pyridin-4-yl-5-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-ethyl)-amine;1-{4-Pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol;1-{4-Pyridin-4-yl-5-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol;2-[4-(2-Isopropyl-4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline;7-Chloro-2-[4-(1-methyl4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline hydrogen chloride;6-Fluoro-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolinehydrogen chloride;2-[2-Fluoro4-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline;2-[2-Fluoro4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline;2-[2,3-Difluoro-4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline;2-[3-Fluoro-4-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline;2-[4-(5-Pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline;2-[4-(1-Methyl-5-pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline2-[4-(1-Methyl-3-pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline;2-Methyl-1-{4-pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol;2-Methyl-1-{4-pyridin-4-yl-5-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol;(R)-1-{4-Pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol;(S)-1-{4-Pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol;2-[4-(1-Isopropyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline;2-[4-(1-Isobutyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline;2-{2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline;2-{2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline;2-{4-[4-(2-Chloro-pyridin-4-yl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline;2-{4-[4-(2-Chloro-pyridin-4-yl)-1-methyl-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline;8-Methoxy-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline;2-[3-Fluoro4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline;4-Chloro-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline;4-Methoxy-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline;Dimethyl-{2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolin-4-yl}-amine;2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyloxy]-quinolinedi-succinic acid;2-((4-(3-Methyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline;2-((4-(1,3-dimethyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline;2-((4-(1,5-dimethyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinoline;2-(1-(4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)ethyl)quinoline;and pharmaceutical acceptable salts thereof.
 6. The compound of claim 1,wherein said compound is selected from a group consisting of:2-{4-[-Pyridin-4-yl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazol-3-yl]-phenoxymethyl}-quinoline;2-{4-[-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline;2-{3-Fluoro-4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline;and pharmaceutical acceptable salts thereof.
 7. A pharmaceuticalcomposition comprising an a compound of formula I according to claim 1and a pharmaceutical acceptable carrier.
 8. The compound of claim 1,wherein said compound is:2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline or apharmaceutical acceptable salt thereof.
 9. The compound of claim 1,wherein said compound is:2-[4-(1-Methyl-4-pyridin-4yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolineor a pharmaceutical acceptable salt thereof.